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| Reference Keyword | |
| J. Comput. Aided Mol. Des., 2002, 16, 769-778 GOLPE | |
| J. Comput. Aided Mol. Des., 2002, 16, 769-778 GRID | |
| J. Comput. Aided Mol. Des., 2002, 16, 769-778 3D-QSAR | |
| J. Comput. Aided Mol. Des., 2002, 16, 769-778 CoMFA | |
| J. Comput. Aided Mol. Des., 2003, 17, 135-153 CoMFA | |
| J. Med. Chem., 2001, 44, 155-169 CoMFA | |
| J. Med. Chem., 2002, 45, 1447-1459 CB1 | |
| J. Med. Chem., 2002, 45, 1447-1459 3D-QSAR | |
| J. Med. Chem., 2002, 45, 2894-2903 3D-QSAR | |
| J. Med. Chem., 2002, 45, 2894-2903 CoMFA | |
| J. Med. Chem., 2002, 45, 2749-2769 3D-QSAR | |
| J. Med. Chem., 2002, 45, 2749-2769 CoMSIA | |
| J. Med. Chem., 2002, 45, 2749-2769 CoMFA | |
| J. Med. Chem., 2006, 49, 6692-6703 3D-QSAR | |
| J. Med. Chem., 2005, 48, 4410-4419 3D-QSAR | |
| J. Med. Chem., 2005, 48, 4410-4419 CoMSIA | |
| J. Med. Chem., 2005, 48, 3290-3312 3D-QSAR | |
| J. Med. Chem., 2004, 47, 1098-1109 3D-QSAR | |
| J. Mol. Graph. Model., 2008, 26, 1169-1178 3D-QSAR | |
| J. Mol. Graph. Model., 2008, 26, 1169-1178 CoMFA | |
| J Chem Inf Model, 2008, 48, 350-363 3D-QSAR | |
| Bioorg. Med. Chem., 2009, 17, 5868-5873 CoMFA | |
| J. Med. Chem., 2002, 45, 2749-2769 CoMFA | |
| J. Med. Chem., 2002, 45, 2894-2903 CoMFA | |
| J. Med. Chem., 2002, 45, 2749-2769 CoMSIA | |
| J. Med. Chem., 2005, 48, 3290-3312 3D-QSAR | |
| J. Med. Chem., 2006, 49, 6692-6703 3D-QSAR | |
| J. Med. Chem., 2002, 45, 2749-2769 3D-QSAR | |
| J. Med. Chem., 2002, 45, 2894-2903 3D-QSAR | |
| J. Med. Chem., 2005, 48, 4783-4792 GRID | |
| ChemMedChem, 2011, 6, 633-653 PPAR | |
| J. Med. Chem., 2005, 48, 4783-4792 NOS-I-III | |
| J. Med. Chem., 2005, 48, 4783-4792 NOS | |
| J. Med. Chem., 2005, 48, 4783-4792 CPCA |
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| Journal Volume Reference | |
| ChemMedChem ChemMedChem, 2011 ChemMedChem, 2011, 6, 633-653 | |
| J. Med. Chem. J. Med. Chem., 2006 J. Med. Chem., 2006, 49, 51-69 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 4783-4792 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 4511-4525 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 3290-3312 | |
| J. Med. Chem. J. Med. Chem., 2002 J. Med. Chem., 2002, 45, 2749-2769 | |
| PLoS ONE PLoS ONE, 2012 PLoS ONE, 2012, 7, e33484 | |
| J. Med. Chem. J. Med. Chem., 2001 J. Med. Chem., 2001, 44, 3407-3416 | |
| Nature Nature, 2001 Nature, 2001, 410, 50-56 | |
| J. Mol. Graph. Model. J. Mol. Graph. Model., 2001 J. Mol. Graph. Model., 2001, 20, 155-167 | |
| J. Med. Chem. J. Med. Chem., 2002 J. Med. Chem., 2002, 45, 2894-2903 | |
| J. Med. Chem. J. Med. Chem., 2002 J. Med. Chem., 2002, 45, 2749-2769 | |
| Science Science, 2003 Science, 2003, 299, 1039-1042 | |
| Bioorg. Med. Chem. Bioorg. Med. Chem., 2003 Bioorg. Med. Chem., 2003, 11, 1107-1115 | |
| J. Am. Chem. Soc. J. Am. Chem. Soc., 2003 J. Am. Chem. Soc., 2003, 125, 3198-3199 | |
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| J. Am. Chem. Soc. J. Am. Chem. Soc., 2005 J. Am. Chem. Soc., 2005, 127, 536-537 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 8098-8102 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 7789-7795 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 6178-6193 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 4783-4792 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 4511-4525 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 3290-3312 | |
| J. Med. Chem. J. Med. Chem., 2005 J. Med. Chem., 2005, 48, 2957-2963 | |
| ChemBioChem ChemBioChem, 2005 ChemBioChem, 2005, 6, 405-413 | |
| J. Med. Chem. J. Med. Chem., 2006 J. Med. Chem., 2006, 49, 6897-6907 | |
| J. Med. Chem. J. Med. Chem., 2006 J. Med. Chem., 2006, 49, 6692-6703 | |
| J. Med. Chem. J. Med. Chem., 2006 J. Med. Chem., 2006, 49, 1828-1832 | |
| J. Med. Chem. J. Med. Chem., 2006 J. Med. Chem., 2006, 49, 51-69 | |
| J. Am. Chem. Soc. J. Am. Chem. Soc., 2006 J. Am. Chem. Soc., 2006, 128, 14485-14497 | |
| J. Med. Chem. J. Med. Chem., 2007 J. Med. Chem., 2007, 50, 5848-5852 | |
| Bioorg. Med. Chem. Bioorg. Med. Chem., 2008 Bioorg. Med. Chem., 2008, 16, 9471-9486 | |
| J. Med. Chem. J. Med. Chem., 2008 J. Med. Chem., 2008, 51, 5594-5607 | |
| J. Med. Chem. J. Med. Chem., 2008 J. Med. Chem., 2008, 51, 752-759 | |
| J. Med. Chem. J. Med. Chem., 2008 J. Med. Chem., 2008, 51, 1053-1057 | |
| Science Science, 2008 Science, 2008, 319, 1391-1394 | |
| J. Am. Chem. Soc. J. Am. Chem. Soc., 2008 J. Am. Chem. Soc., 2008, 130, 17206-17207 | |
| J Chem Inf Model J Chem Inf Model, 2008 J Chem Inf Model, 2008, 48, 1999-2009 | |
| Nature Nature, 2009 Nature, 2009, 460, 405-409 | |
| ChemMedChem ChemMedChem, 2009 ChemMedChem, 2009, 4, 963-966 | |
| ChemMedChem ChemMedChem, 2009 ChemMedChem, 2009, 4, 55-68 | |
| J. Am. Chem. Soc. J. Am. Chem. Soc., 2009 J. Am. Chem. Soc., 2009, 131, 5153-5162 | |
| J. Med. Chem. J. Med. Chem., 2009 J. Med. Chem., 2009, 52, 3869-3880 | |
| PLoS ONE PLoS ONE, 2009 PLoS ONE, 2009, 4, e7436 | |
| PLoS ONE PLoS ONE, 2009 PLoS ONE, 2009, 4, e6202 | |
| PLoS ONE PLoS ONE, 2009 PLoS ONE, 2009, 4, e5136 | |
| PLoS ONE PLoS ONE, 2009 PLoS ONE, 2009, 4, e4769 | |
| J. Med. Chem. J. Med. Chem., 2010 J. Med. Chem., 2010, 53, 1458-1464 | |
| J. Med. Chem. J. Med. Chem., 2010 J. Med. Chem., 2010, 53, 607-615 | |
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| Eur J Med Chem Eur J Med Chem, 2010 Eur J Med Chem, 2010, 45, 870-882 | |
| ChemMedChem ChemMedChem, 2011 ChemMedChem, 2011, 6, 633-653 | |
| J. Med. Chem. J. Med. Chem., 2011 J. Med. Chem., 2011, 54, 4964-4976 | |
| Bioorg. Med. Chem. Bioorg. Med. Chem., 2012 Bioorg. Med. Chem., 2012, 20, 4377-4389 | |
| J. Med. Chem. J. Med. Chem., 2012 J. Med. Chem., 2012, 55, 4788-4805 | |
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| Year Reference Title Summary | |
| 2012 J. Med. Chem., 2012, 55, 4788-4805 Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kbeta inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts. | |
| 2012 PLoS ONE, 2012, 7, e33484 Low prevalence of transmitted drug resistance in patients newly diagnosed with HIV-1 infection in Sweden 2003-2010. Transmitted drug resistance (TDR) is a clinical and epidemiological problem because it may contribute to failure of antiretroviral treatment. The prevalence of TDR varies geographically, and its prevalence in Sweden during the last decade has not been reported. Plasma samples from 1,463 patients newly diagnosed with HIV-1 infection between 2003 and 2010, representing 44% of all patients diagnosed in Sweden during this period, were analyzed using the WHO 2009 list of mutations for surveillance of TDR. Maximum likelihood phylogenetic analyses were used to determine genetic subtype and to investigate the relatedness of the sequences. Eighty-two patients showed evidence of TDR, representing a prevalence of 5.6% (95% CI: 4.5%-6.9%) without any significant time trends or differences between patients infected in Sweden or abroad. Multivariable logistic regression showed that TDR was positively associated with men who have sex with men (MSM) and subtype B infection and negatively associated with CD4 cell counts. Among patients with TDR, 54 (68%) had single resistance mutations, whereas five patients had multi-drug resistant HIV-1. Phylogenetic analyses identified nine significantly supported clusters involving 29 of the patients with TDR, including 23 of 42 (55%) of the patients with TDR acquired in Sweden. One cluster contained 18 viruses with a M41L resistance mutation, which had spread among MSM in Stockholm over a period of at least 16 years (1994-2010). Another cluster, which contained the five multidrug resistant viruses, also involved MSM from Stockholm. The prevalence of TDR in Sweden 2003-2010 was lower than in many other European countries. TDR was concentrated among MSM, where clustering of TDR strains was observed, which highlights the need for continued and improved measures for targeted interventions. | |
| 2009 PLoS ONE, 2009, 4, e4769 SpeB of Streptococcus pyogenes differentially modulates antibacterial and receptor activating properties of human chemokines. BACKGROUND: CXC chemokines are induced by inflammatory stimuli in epithelial cells and some, like MIG/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11, are antibacterial for Streptococcus pyogenes. METHODOLOGY/PRINCIPAL FINDINGS: SpeB from S. pyogenes degrades a wide range of chemokines (i.e. IP10/CXCL10, I-TAC/CXCL11, PF4/CXCL4, GROalpha/CXCL1, GRObeta/CXCL2, GROgamma/CXCL3, ENA78/CXCL5, GCP-2/CXCL6, NAP-2/CXCL7, SDF-1/CXCL12, BCA-1/CXCL13, BRAK/CXCL14, SRPSOX/CXCL16, MIP-3alpha/CCL20, Lymphotactin/XCL1, and Fractalkine/CX3CL1), has no activity on IL-8/CXCL8 and RANTES/CCL5, partly degrades SRPSOX/CXCL16 and MIP-3alpha/CCL20, and releases a 6 kDa CXCL9 fragment. CXCL10 and CXCL11 loose receptor activating and antibacterial activities, while the CXCL9 fragment does not activate the receptor CXCR3 but retains its antibacterial activity. CONCLUSIONS/SIGNIFICANCE: SpeB destroys most of the signaling and antibacterial properties of chemokines expressed by an inflamed epithelium. The exception is CXCL9 that preserves its antibacterial activity after hydrolysis, emphasizing its role as a major antimicrobial on inflamed epithelium. | |
| 2003 Science, 2003, 299, 1039-1042 Crystal structure of naphthalene dioxygenase: side-on binding of dioxygen to iron. Binding of oxygen to iron is exploited in several biological and chemical processes. Although computational and spectroscopic results have suggested side-on binding, only end-on binding of oxygen to iron has been observed in crystal structures. We have determined structures of naphthalene dioxygenase that show a molecular oxygen species bound to the mononuclear iron in a side-on fashion. In a complex with substrate and dioxygen, the dioxygen molecule is lined up for an attack on the double bond of the aromatic substrate. The structures reported here provide the basis for a reaction mechanism and for the high stereospecificity of the reaction catalyzed by naphthalene dioxygenase. | |
| 2012 Bioorg. Med. Chem., 2012, 20, 4377-4389 Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: design, synthesis and X-ray crystal structures of enzyme inhibitor complexes. A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed. | |
| 2010 J. Med. Chem., 2010, 53, 1458-1464 Design and synthesis of potent and selective BACE-1 inhibitors. 1000-fold selectivity over cathepsin D. | |
| 2010 Bioorg. Med. Chem., 2010, 18, 1711-1723 Discovery of potent BACE-1 inhibitors containing a new hydroxyethylene (HE) scaffold: exploration of P1` alkoxy residues and an aminoethylene (AE) central core. 1500) dropped for larger groups (P1`=benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity. | |
| 2010 Eur J Med Chem, 2010, 45, 870-882 Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core. We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2`-P3` position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1`-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC(50) value of 3.1 nM. | |
| 2008 Bioorg. Med. Chem., 2008, 16, 9471-9486 Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues. Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors. | |
| 2003 Bioorg. Med. Chem., 2003, 11, 1107-1115 Design and synthesis of HIV-1 protease inhibitors. Novel tetrahydrofuran P2/P2`-groups interacting with Asp29/30 of the HIV-1 protease. Determination of binding from X-ray crystal structure of inhibitor protease complex. A series of HIV-1 protease inhibitors having new tetrahydrofuran P2/P2` groups have been synthesised and tested for protease inhibition and antiviral activity. Six novel 4-aminotetrahydrofuran derivatives were prepared starting from commercially available isopropylidene-alpha-D-xylofuranose yielding six symmetrical and six unsymmetrical inhibitors. Promising sub nanomolar HIV-1 protease inhibitory activities were obtained. The X-ray crystal structure of the most potent inhibitor (23, K(i) 0.25 nM) co-crystallised with HIV-1 protease is discussed and the binding compared with inhibitors 1a and 1b. | |
| 2001 J. Med. Chem., 2001, 44, 3407-3416 Synthesis of novel, potent, diol-based HIV-1 protease inhibitors via intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal. The synthesis of novel, potent, diol-based HIV-1 protease inhibitors, having phenethyl groups (-CH(2)CH(2)Ph) in P1/P1` position is described. An intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal 16 was the key step in the synthesis. From this reaction sequence four carba analogues, compounds 8a, 8b, 9a, and 9b, were prepared, having the inverted configuration of one or both of the stereogenic centers carrying the diol hydroxyls as compared to the parent series represented by inhibitors 6 and 7. Inhibitor 8b was found to be a potent inhibitor of HIV-1 protease (PR), showing excellent antiviral activity in the cell-based assay and in the presence of 40% human serum. The absolute stereochemistry of the central diol of the potent inhibitor (8b) was determined from the X-ray crystallographic structure of its complex with HIV-1 PR. | |
| 2011 J. Med. Chem., 2011, 54, 4964-4976 Design, synthesis, and X-ray crystallographic studies of alpha-aryl substituted fosmidomycin analogues as inhibitors of Mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate reductoisomerase. 32 μg/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite. | |
| 2010 J. Med. Chem., 2010, 53, 607-615 HIV-1 protease inhibitors with a transition-state mimic comprising a tertiary alcohol: improved antiviral activity in cells. By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1` side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease. | |
| 2008 J. Med. Chem., 2008, 51, 1053-1057 Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic. A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1` group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported. | |
| 2006 J. Med. Chem., 2006, 49, 1828-1832 Microwave-accelerated synthesis of P1`-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold. Two series of P1`-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1` side chain. High cellular antiviral potencies were encountered when the P1` benzyl group was elongated with a 3-or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme. | |
| 2005 J. Med. Chem., 2005, 48, 8098-8102 A new class of HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold. Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1`-P3` residues and alteration of the tertiary alcohol absolute stereochemistry afforded 10 inhibitors. High potencies for the compounds with (S)-configuration at the carbon carrying the tertiary hydroxyl group were achieved with Ki values down to 2.4 nM. X-ray crystallographic data for a representative compound in complex with HIV-1 protease are presented. | |
| 2012 J. Med. Chem., 2012, 55, 2894-2898 Trisubstituted imidazoles as Mycobacterium tuberculosis glutamine synthetase inhibitors. Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC(50) values and promising antituberculosis MIC values. | |
| 2009 ChemMedChem, 2009, 4, 963-966 Fragment-based identification of Hsp90 inhibitors. Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high-concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure-based drug design (SBDD) approach. | |
| 2005 ChemBioChem, 2005, 6, 405-413 A new type of metalloprotein: the Mo storage protein from Azotobacter vinelandii contains a polynuclear molybdenum-oxide cluster. Azotobacter vinelandii is a diazotrophic bacterium characterized by the outstanding capability of storing Mo in a special storage protein, which guarantees Mo-dependent nitrogen fixation even under growth conditions of extreme Mo starvation. The Mo storage protein is constitutively synthesized with respect to the nitrogen source and is regulated by molybdenum at an extremely low concentration level (0-50 nM). This protein was isolated as an alpha4beta4 octamer with a total molecular mass of about 240 kg mol(-1) and its shape was determined by small-angle X-ray scattering. The genes of the alpha and beta subunits were unequivocally identified; the amino acid sequences thereby determined reveal that the Mo storage protein is not related to any other known molybdoprotein. Each protein molecule can store at least 90 Mo atoms. Extended X-ray absorption fine-structure spectroscopy identified a metal-oxygen cluster bound to the Mo storage protein. The binding of Mo (biosynthesis and incorporation of the cluster) is dependent on adenosine triphosphate (ATP); Mo release is ATP-independent but pH-regulated, occurring only above pH 7.1. This Mo storage protein is the only known noniron metal storage system in the biosphere containing a metal-oxygen cluster. | |
| 2001 Nature, 2001, 410, 50-56 Involvement of chemokine receptors in breast cancer metastasis. Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells. | |
| 2001 J. Mol. Graph. Model., 2001, 20, 155-167 Homology modeling of the estrogen receptor subtype beta (ER-beta) and calculation of ligand binding affinities. 60%), we have developed a homology model of the ER-beta structure. Using the crystal structure of ER-alpha and the homology model of ER-beta, we demonstrate a strong correlation between computed values of the binding-energy and published values of the observed relative binding affinity (RBA) for a variety of compounds for both receptors, as well as the ability to identify receptor subtype selective compounds. Furthermore, using the recently available crystal structure of ER-beta for comparison purposes, we show that not only is the predicted homology model structurally accurate, but that it can be used to assess ligand binding affinities. | |
| 2009 PLoS ONE, 2009, 4, e7436 The Imd pathway is involved in antiviral immune responses in Drosophila. Cricket Paralysis virus (CrPV) is a member of the Dicistroviridae family of RNA viruses, which infect a broad range of insect hosts, including the fruit fly Drosophila melanogaster. Drosophila has emerged as an effective system for studying innate immunity because of its powerful genetic techniques and the high degree of gene and pathway conservation. Intra-abdominal injection of CrPV into adult flies causes a lethal infection that provides a robust assay for the identification of mutants with altered sensitivity to viral infection. To gain insight into the interactions between viruses and the innate immune system, we injected wild type flies with CrPV and observed that antimicrobial peptides (AMPs) were not induced and hemocytes were depleted in the course of infection. To investigate the contribution of conserved immune signaling pathways to antiviral innate immune responses, CrPV was injected into isogenic mutants of the Immune Deficiency (Imd) pathway, which resembles the mammalian Tumor Necrosis Factor Receptor (TNFR) pathway. Loss-of-function mutations in several Imd pathway genes displayed increased sensitivity to CrPV infection and higher CrPV loads. Our data show that antiviral innate immune responses in flies infected with CrPV depend upon hemocytes and signaling through the Imd pathway. | |
| 2005 J. Med. Chem., 2005, 48, 4511-4525 Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography. Structure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structural requirements for addressing subpockets of the factor Xa enzyme. Interactions with the subpockets were probed by systematic substitution of the 2-carboxyindole scaffold, in combination with privileged P1 and P4 substituents. Combining the most favorable substituents at the indole nucleus led to the discovery of a remarkably potent factor Xa inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of inhibitors bound to factor Xa revealed substituent-dependent switching of the inhibitor binding mode and provided a rationale for the SAR obtained. These results underscore the key role played by the P1 ligand not only in determining the binding affinity of the inhibitor by direct interaction but also in modifying the binding mode of the whole scaffold, resulting in a nonlinear SAR. | |
| 2002 J. Med. Chem., 2002, 45, 2749-2769 Design and quantitative structure-activity relationship of 3-amidinobenzyl-1H-indole-2-carboxamides as potent, nonchiral, and selective inhibitors of blood coagulation factor Xa. A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa) were designed, synthesized, and investigated by X-ray structure analysis and 3D quantitative structure-activity relationship (QSAR) studies (CoMFA, CoMSIA) in order to identify important protein-ligand interactions responsible for biological affinity and selectivity. Several compounds from this series are highly potent and selective inhibitors of this important enzyme linking extrinsic and intrinsic coagulation pathways. To rationalize biological affinity and to provide guidelines for further design, all compounds were docked into the factor Xa binding site. Those docking studies were based on X-ray structures of factor Xa in complex with literature-known inhibitors. It was possible to validate those binding modes by four X-ray crystal structures of representative ligands in factor Xa, while one ligand was additionally crystallized in trypsin to rationalize requirements for selective factor Xa inhibition. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r(2) values using the leave-one-out method and repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined factor Xa binding site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. The final quantitative SAR information agrees with all experimental data for the binding topology and thus provides reasonable activity predictions for novel factor Xa inhibitors. | |
| 2005 J. Med. Chem., 2005, 48, 3290-3312 Structural requirements for factor Xa inhibition by 3-oxybenzamides with neutral P1 substituents: combining X-ray crystallography, 3D-QSAR, and tailored scoring functions. The design, synthesis, and structure-activity relationship of 3-oxybenzamides as potent inhibitors of the coagulation protease factor Xa are described on the basis of X-ray structures, privileged structure motifs, and SAR information. A total of six X-ray structures of fXa/inhibitor complexes led us to identify the major protein-ligand interactions. The binding mode is characterized by a lipophilic dichlorophenyl substituent interacting with Tyr228 in the protease S1 pocket, while polar parts are accommodated in S4. This alignment in combination with docking allowed derivation of 3D-QSAR models and tailored scoring functions to rationalize biological affinity and provide guidelines for optimization. The resulting models showed good correlation coefficients and predictions of external test sets. Furthermore, they correspond to binding site topologies in terms of steric, electrostatic, and hydrophobic complementarity. Two approaches to derive tailored scoring functions combining binding site and ligand information led to predictive models with acceptable predictions of the external set. Good correlations to experimental affinities were obtained for both AFMoC (adaptation of fields for molecular comparison) and the novel TScore function. The SAR information from 3D-QSAR and tailored scoring functions agrees with all experimental data and provides guidelines and reasonable activity estimations for novel fXa inhibitors. | |
| 2005 J. Med. Chem., 2005, 48, 6178-6193 Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chemical optimization supported by X-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23 +/-1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chemical features for the biological activity and (ii) the 1.9 angstroms crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53 +/-1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anaesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes. | |
| 2011 ChemMedChem, 2011, 6, 633-653 Sulfonylthiadiazoles with an unusual binding mode as partial dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonists with high potency and in vivo efficacy. Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high-throughput screening as a moderate partial PPARδ agonist; its optimization was based on the X-ray crystal structure in complex with PPARδ. In contrast to other PPARδ agonists, this ligand does not interact directly with residues from the activation helix AF-2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20 a, displayed EC₅₀ values of 1.6 and 336 nM for PPARδ and γ, respectively. The X-ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20 a clearly displayed in vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre-diabetic db/db mice. However, body weight gain was similar to that observed with the PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome. | |
| 2006 J. Med. Chem., 2006, 49, 51-69 Matrix metalloproteinase target family landscape: a chemometrical approach to ligand selectivity based on protein binding site analysis. S1, S2`. The interpretation of these models agreed with experimental binding modes inferred from crystal structures or docking. | |
| 2005 J. Med. Chem., 2005, 48, 4783-4792 Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases. Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms (NOS-I-III) is physiologically important but also can be deleterious when overproduced. Selective NOS inhibitors are of clinical interest, given their differing pathophysiological roles. Here we describe our approach to target the unique NOS (6R,1`R,2`S)-5,6,7,8-tetrahydrobiopterin (H(4)Bip) binding site. By a combination of ligand- and structure-based design, the structure-activity relationship (SAR) for a focused set of 41 pteridine analogues on four scaffolds was developed, revealing selective NOS-I inhibitors. The X-ray crystal structure of rat NOS-I dimeric-oxygenase domain with H(4)Bip and l-arginine was determined and used for human isoform homology modeling. All available NOS structural information was subjected to comparative analysis of favorable protein-ligand interactions using the GRID/concensus principal component analysis (CPCA) approach to identify the isoform-specific interaction site. Our interpretation, based on protein structures, is in good agreement with the ligand SAR and thus permits the rational design of next-generation inhibitors targeting the H(4)Bip binding site with enhanced isoform selectivity for therapeutics in pathology with NO overproduction. | |
| 2012 J. Med. Chem., 2012, 55, 4367-4372 Head-to-head prenyl tranferases: anti-infective drug targets. We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine headgroup binds in the allylic (S1) site with the side chain in S2, but in the presence of PPi and Mg(2+), the quinuclidine`s cationic center interacts with PPi and three Mg(2+), mimicking a transition state involved in diphosphate ionization. With 3, there are again two structures. In one, the geranyl side chain binds to either S1 or S2 and the adamantane headgroup binds to S1. In the second, the side chain binds to S2 while the headgroup binds to S1. These results provide structural clues for the mechanism and inhibition of the head-to-head prenyl transferases and should aid future drug design. | |
| 2009 J. Med. Chem., 2009, 52, 3869-3880 Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results. The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar K(i) values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC(50) = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections. | |
| 2009 J. Am. Chem. Soc., 2009, 131, 5153-5162 Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation. Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS. | |
| 2008 J. Am. Chem. Soc., 2008, 130, 17206-17207 Structure of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate reductase, the terminal enzyme of the non-mevalonate pathway. Molecular evolution has evolved two metabolic routes for isoprenoid biosynthesis: the mevalonate and the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway. The MEP pathway is used by most pathogenic bacteria and some parasitic protozoa (including the malaria parasite, Plasmodium falciparum) as well as by plants, but is not present in animals. The terminal reaction of the MEP pathway is catalyzed by (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) reductase (LytB), an enzyme that converts HMBPP into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Here, we present the structure of Aquifex aeolicus LytB, at 1.65 A resolution. The protein adopts a cloverleaf or trefoil-like structure with each monomer in the dimer containing three alpha/beta domains surrounding a central [Fe3S4] cluster ligated to Cys13, Cys96, and Cys193. Two highly conserved His (His 42 and His 124) and a totally conserved Glu (Glu126) are located in the same central site and are proposed to be involved in ligand binding and catalysis. Substrate access is proposed to occur from the front-side face of the protein, with the HMBPP diphosphate binding to the two His and the 4OH of HMBPP binding to the fourth iron thought to be present in activated clusters, while Glu126 provides the protons required for IPP/DMAPP formation. | |
| 2008 J. Med. Chem., 2008, 51, 5594-5607 Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. We report the X-ray structures of several bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, a target for anticancer drugs. Bisphosphonates containing unbranched side chains bind to either the farnesyl diphosphate (FPP) substrate site, the geranylgeranyl diphosphate (GGPP) product site, and in one case, both sites, with the bisphosphonate moiety interacting with 3 Mg (2+) that occupy the same position as found in FPP synthase. However, each of three `V-shaped` bisphosphonates bind to both the FPP and GGPP sites. Using the Glide program, we reproduced the binding modes of 10 bisphosphonates with an rms error of 1.3 A. Activities of the bisphosphonates in GGPPS inhibition were predicted with an overall error of 2x by using a comparative molecular similarity analysis based on a docked-structure alignment. These results show that some GGPPS inhibitors can occupy both substrate and product site and that binding modes as well as activity can be accurately predicted, facilitating the further development of GGPPS inhibitors as anticancer agents. | |
| 2008 Science, 2008, 319, 1391-1394 A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration approximately 100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor-based therapy against S. aureus. | |
| 2006 J. Am. Chem. Soc., 2006, 128, 14485-14497 Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes. Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseases and are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), but the details of how these molecules bind are not fully understood. Here, we report the results of a solid-state (13)C, (15)N, and (31)P magic-angle sample spinning (MAS) NMR and quantum chemical investigation of several bisphosphonates, both as pure compounds and when bound to FPPS, to provide information about side-chain and phosphonate backbone protonation states when bound to the enzyme. We then used computational docking methods (with the charges assigned by NMR) to predict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determine the structures of two potent bisphosphonate inhibitors, finding good agreement with the computational results, opening up the possibility of using the combination of NMR, quantum chemistry and molecular docking to facilitate the design of other, novel prenytransferase inhibitors. | |
| 2005 J. Med. Chem., 2005, 48, 2957-2963 Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption. We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs. | |
| 2005 J. Am. Chem. Soc., 2005, 127, 536-537 A crystallographic investigation of phosphoantigen binding to isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase. We report the crystallographic structures of the potent phosphoantigens Phosphostim (the bromohydrin of isopentenyl pyrophosphate) and E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate bound to the mevalonate pathway enzyme isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase (IPPI). Racemic Phosphostim forms covalent complexes with IPPI: a 4-thioether with C67 and a 4-ester with E116. Only the E116 ester forms with the chiral species, S-Phosphostim, with the w.t. enzyme, while the C67 thioether forms with a mutant Y104F IPPI. The potent phosphoantigen HMBPP also binds to IPPI, but is only a weak ( approximately 50 muM) inhibitor. These results strongly support an SN2 reaction for inhibition of IPPI by Phosphostim, in contrast to the SN1 or concerted type of reaction found with epoxide inhibitors, which react at C-3, and are of general interest in the context of the development of novel mevalonate pathway inhibitors. They also provide clues as to the nature of the binding site of synthetic phosphoantigens in gammadelta T cell activation. In particular, both bromohydrin and epoxy phosphoantigens are potent, irreversible inhibitors of IPPI while HMBPP is only a weak inhibitor, ruling out an IPPI or IPPI-like target for HMBPP in gammadelta T cell activation. | |
| 2004 J. Am. Chem. Soc., 2004, 126, 10824-10825 Crystallographic structures of two bisphosphonate:1-deoxyxylulose-5-phosphate reductoisomerase complexes. We have obtained the single-crystal X-ray crystallographic structures of the bisphosphonates [(1-isoquinolinylamino)methylene]-1,1-bisphosphonate and [[(5-chloro-2-pyridinyl)amino]methylene]-1,1-bisphosphonate, bound to the enzyme 1-deoxyxylulose-5-phosphate reductoisomerase (DXR, EC 1.1.1.267, also known as 2-C-methyl-d-erythritol-4-phosphate synthase), an important target for the development of antimalarial drugs. Our results indicate that both bisphosphonates bind into the fosmidomycin binding site. The aromatic groups are in a shallow hydrophobic pocket, and the phosphonate groups are involved in electrostatic interactions with Mg2+ or a cluster of carboxylic acid groups and lysine while the fosmidomycin phosphonate-binding site is occupied by a sulfate ion (as also observed in the DXR/NADP+ structure). The availability of these two new crystal structures opens up the possibility of the further development of bisphosphonates and related systems as DXR inhibitors and, potentially, as antiinfective agents. | |
| 2003 J. Am. Chem. Soc., 2003, 125, 3198-3199 Structure and mechanism of action of isopentenylpyrophosphate-dimethylallylpyrophosphate isomerase. We have obtained the three-dimensional X-ray crystallographic structure of a C67A mutant Escherichia coli isopentenylpyrophosphate-dimethylallylpyrophosphate isomerase (EC 5.3.3.2) complexed with the bromohydrin of isopentenylpyrophosphate, at 1.93 A resolution. The overall backbone fold is very similar to that obtained previously for the wild-type enzyme in the presence of a divalent metal cation (Mn2+ or Mg2+). However, in the new structure, there are two metal binding sites, not just one. The first metal binding site is occupied by Mn2+, coordinated to three histidine and two glutamate residues, while the second is occupied by Mg2+, coordinated to two bromohydrin-ligand phosphate oxygens, the carbonyl oxygen of A67, a carboxyl oxygen of E87, and two water molecules. The C3 hydroxyl group of the bromohydrin inhibitor is involved in a short hydrogen bond to the carboxyl group of E116, one of the two Mn-bound glutamates. The structure obtained is consistent with a mechanism of action of the enzyme in which the carboxyl group of E116 protonates the double bond in isopentenylpyrophosphate, forming a carbocation, followed by removal of a C2 proton by the thiolate of C67, in the wild-type enzyme. The inhibition of the enzyme by a wide variety of other potent inhibitors is also readily explained on the basis of the bromohydrin inhibitor structure. | |
| 2002 J. Med. Chem., 2002, 45, 2894-2903 An investigation of bone resorption and Dictyostelium discoideum growth inhibition by bisphosphonate drugs. We report the results of 3D-QSAR/CoMFA investigations of the activity of bisphosphonate drugs, farnesyl pyrophosphate synthase (FPPSase) inhibitors, in the inhibition of bone resorption as well as the growth of Dictyostelium discoideum. In the case of D. discoideum, we find an experimental versus QSAR predicted pIC(50) R(2) value of 0.94 for 16 bisphosphonates over the 9-1200 microM range of IC(50) values, a cross-validated R(2) = 0.90, and a bootstrapped R(2) = 0.94, and we demonstrate that this approach has predictive utility (a 0.18 pIC(50) rms error for three test sets of 3 predictions). In bone resorption, we find an experimental versus predicted pLED (lowest effective dose) R(2) = 0.79 for 35 bisphosphonates over the 0.0001-1 mg of P/kg LED range, a cross-validated R(2) = 0.75, and a bootstrapped R(2) = 0.79. Two sets of 31 compounds were used as training sets for the predicted pLED values for two sets of 4 compounds which have an rms error of 0.44, larger than that found with D. discoideum. However, this can be attributed to the rather large uncertainties in the experimental bone resorption data which are almost all reported in decade steps (DeltapLED = 1). The CoMFA predicted (rat) bone antiresorptive pLED values are in agreement with literature (human recombinant) FPPSase inhibition results with an rms error of 0.45 (a factor of 2.8 error in activity prediction). We also report the single-crystal X-ray crystallographic structure of the compound most active in D. discoideum growth inhibition, 2-(3-picolyl)-aminomethylene-1,1-bisphosphonic acid. The structure clearly shows the presence of bond length alternation in the picolyl ring and a planar amino group linked by a very short (1.346 A) bond to the picolyl group, an amidinium-like structure which is also expected to occur in other highly active species such as minodronate and zoledronate. Overall, these results show that it is now possible to predict the activity of bisphosphonates using 3D-QSAR/CoMFA methods, although bone resorption studies should benefit from additional, accurate information on enzyme inhibition. | |
| 2006 J. Med. Chem., 2006, 49, 6692-6703 Bisphosphonate inhibition of phosphoglycerate kinase: quantitative structure-activity relationship and pharmacophore modeling investigation. We report the results of a three-dimensional quantitative structure-activity relationship (3D-QSAR) and pharmacophore modeling investigation of the interaction of the enzyme 3-phosphoglycerate kinase (PGK) with aryl and alkyl bisphosphonates. For the human enzyme, the IC50 values are predicted within a factor of 2 over the 240x experimental range in activity, while for the yeast enzyme, binding of the more flexible alkyl bisphosphonates is predicted within a factor of approximately 4 (over a 2500x range in activity). Pharmacophore models indicate the importance of two negative ionizable features, one hydrophobic feature, and one halogen feature, and docking studies indicate that bisphosphonates bind in a manner similar to the 3-phosphoglycerate molecule identified crystallographically. The results give a good account of the activities of a diverse range of bisphosphonate inhibitors and are of interest in the context of developing inhibitors of glycolysis in organisms that are totally reliant on glycolysis for ATP production, such as trypanosomatid parasites. | |
| 2008 J Chem Inf Model, 2008, 48, 1999-2009 Targeting the conformational transitions of MDM2 and MDMX: insights into dissimilarities and similarities of p53 recognition. MDM2 and MDMX are oncogenic homologue proteins that regulate the activity and stability of p53, a tumor suppressor protein involved in more than 50% of human cancers. While the large body of experiments so far accumulated has validated MDM2 as a therapeutically important target for the development of anticancer drugs, it is only recently that MDMX has also become an attractive target for the treatment of tumor cells expressing wild type p53. The availability of structural information of the N-terminal domain of MDM2 in complex with p53-derived peptides and inhibitors, and the very recent disclosure of the crystal structure of the N-terminal domain of MDMX bound to a p53 peptide, offer an unprecedented opportunity to provide insight into the molecular basis of p53 recognition and the identification of discriminating features affecting the binding of the tumor suppressor protein at MDM2 and MDMX. By using coarse graining simulations, in this study we report the exploration of the conformational transitions featured in the pathway leading from the apo-MDM2 and apo-MDMX states to the p53-bound MDM2 and p53-bound MDMX states, respectively. The results have enabled us to identify a pool of diverse conformational states of the oncogenic proteins that affect the binding of p53 and the presence of conserved and non-conserved interactions along the conformational transition pathway that may be exploited in the design of selective and dual modulators of MDM2 and MDMX activity. | |
| 2007 J. Med. Chem., 2007, 50, 5848-5852 Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. Structures of human monoamine oxidase B (MAO B) in complex with safinamide and two coumarin derivatives, all sharing a common benzyloxy substituent, were determined by X-ray crystallography. These compounds competitively inhibit MAO B with Ki values in the 0.1-0.5 microM range that are 30-700-fold lower than those observed with MAO A. The inhibitors bind noncovalently to MAO B, occupying both the entrance and the substrate cavities and showing a similarly oriented benzyloxy substituent. | |
| 2010 J. Am. Chem. Soc., 2010, 132, 6827-6833 Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. LSD1 and LSD2 histone demethylases are implicated in a number of physiological and pathological processes, ranging from tumorigenesis to herpes virus infection. A comprehensive structural, biochemical, and cellular study is presented here to probe the potential of these enzymes for epigenetic therapies. This approach employs tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. This drug is a clinically validated antidepressant known to target monoamine oxidases A and B. These two flavoenzymes are structurally related to LSD1 and LSD2. Mechanistic and crystallographic studies of tranylcypromine inhibition reveal a lack of selectivity and differing covalent modifications of the FAD cofactor depending on the enantiomeric form. These findings are pharmacologically relevant, since tranylcypromine is currently administered as a racemic mixture. A large set of tranylcypromine analogues were synthesized and screened for inhibitory activities. We found that the common evolutionary origin of LSD and MAO enzymes, despite their unrelated functions and substrate specificities, is reflected in related ligand-binding properties. A few compounds with partial enzyme selectivity were identified. The biological activity of one of these new inhibitors was evaluated with a cellular model of acute promyelocytic leukemia chosen since its pathogenesis includes aberrant activities of several chromatin modifiers. Marked effects on cell differentiation and an unprecedented synergistic activity with antileukemia drugs were observed. These data demonstrate that these LSD1/2 inhibitors are of potential relevance for the treatment of promyelocytic leukemia and, more generally, as tools to alter chromatin state with promise of a block of tumor progression. | |
| 2009 PLoS ONE, 2009, 4, e5136 The anti-apoptotic activity of BAG3 is restricted by caspases and the proteasome. BACKGROUND: Caspase-mediated cleavage and proteasomal degradation of ubiquitinated proteins are two independent mechanisms for the regulation of protein stability and cellular function. We previously reported BAG3 overexpression protected ubiquitinated clients, such as AKT, from proteasomal degradation and conferred cytoprotection against heat shock. We hypothesized that the BAG3 protein is regulated by proteolysis. METHODOLOGY/PRINCIPAL FINDINGS: Staurosporine (STS) was used as a tool to test for caspase involvement in BAG3 degradation. MDA435 and HeLa human cancer cell lines exposed to STS underwent apoptosis with a concomitant time and dose-dependent loss of BAG3, suggesting the survival role of BAG3 was subject to STS regulation. zVAD-fmk or caspase 3 and 9 inhibitors provided a strong but incomplete protection of both cells and BAG3 protein. Two putative caspase cleavage sites were tested: KEVD (BAG3(E345A/D347A)) within the proline-rich center of BAG3 (PXXP) and the C-terminal LEAD site (BAG3(E516A/D518A)). PXXP deletion mutant and BAG3(E345A/D347A), or BAG3(E516A/D518A) respectively slowed or stalled STS-mediated BAG3 loss. BAG3, ubiquitinated under basal growth conditions, underwent augmented ubiquitination upon STS treatment, while there was no increase in ubiquitination of the BAG3(E516A/D518A) caspase-resistant mutant. Caspase and proteasome inhibition resulted in partial and independent protection of BAG3 whereas inhibitors of both blocked BAG3 degradation. STS-induced apoptosis was increased when BAG3 was silenced, and retention of BAG3 was associated with cytoprotection. CONCLUSIONS/SIGNIFICANCE: BAG3 is tightly controlled by selective degradation during STS exposure. Loss of BAG3 under STS injury required sequential caspase cleavage followed by polyubiquitination and proteasomal degradation. The need for dual regulation of BAG3 in apoptosis suggests a key role for BAG3 in cancer cell resistance to apoptosis. | |
| 2006 J. Med. Chem., 2006, 49, 6897-6907 Small-molecule inhibitors of histone acetyltransferase activity: identification and biological properties. Starting from a yeast phenotypic screening performed on 21 compounds, we described the identification of two small molecules (9 and 18) able to significantly reduce the S. cerevisiae cell growth, thus miming the effect of GCN5 deletion mutant. Tested on a GCN5-dependent gene transcription assay, compounds 9 and 18 gave a high reduction of the reporter activity. In S. cerevisiae histone H3 terminal tails assay, the H3 acetylation levels were highly reduced by treatment with 0.6-1 mM 9, while 18 was effective only at 1.5 mM. In human leukemia U937 cell line, at 1 mM 9 and 18 showed effects on cell cycle (arrest in G1 phase, 9), apoptosis (9), and granulocytic differentiation (18). When tested on U937 cell nuclear extracts to evaluate their histone acetyltransferase (HAT) inhibitory action, both compounds were able to reduce the enzyme activity when used at 500 microM. Another quinoline, compound 22, was synthesized with the aim to improve the activity observed with 9 and 18. Tested in the HAT assay, 22 was able to reduce the HAT catalytic action at 50 and 25 microM, thereby being comparable to anacardic acid, curcumin, and MB-3 used as references. Finally, in U937 cells, compounds 9 and 18 used at 2.5 mM were able to reduce the extent of the acetylation levels of histone H3 (9) and alpha-tubulin (9 and 18). In the same assay, 22 at lower concentration (100 microM) showed the same hypoacetylating effects with both histone and non-histone substrates. | |
| 2005 J. Med. Chem., 2005, 48, 7789-7795 Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Two analogues, namely, 3- and 4-[(2-hydroxy-1-naphthalenylmethylene)amino]-N-(1-phenylethyl)benzamide (i.e., m- and p-sirtinol), were 2-to 10-fold more potent than sirtinol against human SIRT1 and SIRT2 enzymes. In yeast in vivo assay, these two small molecules were as potent as sirtinol. Compounds lacking the 2-hydroxy group at the naphthalene moiety or bearing several modifications at the benzene 2`-position of the aniline portion (carbethoxy, carboxy, and cyano) were 1.3-13 times less potent than sirtinol, whereas the 2`-carboxamido analogue was totally inactive. Both (R)- and (S)-sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect. | |
| 2004 J. Med. Chem., 2004, 47, 1351-1359 3-(4-aroyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides as a new class of synthetic histone deacetylase inhibitors. 3. Discovery of novel lead compounds through structure-based drug design and docking studies. Aroyl-pyrrole-hydroxy-amides (APHAs) are a new class of synthetic HDAC inhibitors recently described by us. Through three different docking procedures we designed, synthesized, and tested two new isomers of APHA lead compound 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1), compounds 3 and 4, characterized by different insertions of benzoyl and propenoylhydroxamate groups onto the pyrrole ring. Biological activities of 3 and 4 were predicted by computational tools up to 617-fold more potent than that of 1 against HDAC1; thus, 3 and 4 were synthesized and tested against both mouse HDAC1 and maize HD2 enzymes. Predictions of biological affinities (K(i) values) of 3 and 4, performed by a VALIDATE model (applied on either SAD or automatic DOCK or Autodock results) and by the Autodock internal scoring function, were in good agreement with experimental activities. Ligand/receptor positive interactions made by 3 and 4 into the catalytic pocket, in addition to those showed by 1, could at least in part account for their higher HDAC1 inhibitory activities. In particular, in mouse HDAC1 inhibitory assay 3 and 4 were 19- and 6-times more potent than 1, respectively, and 3 and 4 antimaize HD2 activities were 16- and 76-times higher than that of 1, 4 being as potent as SAHA in this assay. Compound 4, tested as antiproliferative and cytodifferentiating agent on MEL cells, showed dose-dependent growth inhibition and hemoglobin accumulation effects. | |
| 2009 ChemMedChem, 2009, 4, 55-68 Semi-synthetic ecdysteroids as gene-switch actuators: synthesis, structure-activity relationships, and prospective ADME properties. The ligand-inducible, ecdysteroid receptor (EcR) gene-expression system can add critical control features to protein expression in cell and gene therapy. However, potent natural ecdysteroids possess absorption, distribution, metabolism and excretion (ADME) properties that have not been optimised for use as gene-switch actuators in vivo. Herein we report the first systematic synthetic exploration of ecdysteroids toward modulation of gene-switch potency. Twenty-three semi-synthetic O-alkyl ecdysteroids were assayed in both a natural insect system (Drosophila B(II) cells) and engineered gene-switch systems in mammalian cells using Drosophila melanogaster, Choristoneura fumiferana, and Aedes aegypti EcRs. Gene-switch potency is maintained, or even enhanced, for ecdysteroids methylated at the 22-position in favourable cases. Furthermore, trends toward lower solubility, higher permeability, and higher blood-brain barrier penetration are supported by predicted ADME properties, calculated using the membrane-interaction (MI)-QSAR methodology. The structure-activity relationship (SAR) of alkylated ecdysteroids indicates that 22-OH is an H-bond acceptor, 25-OH is most likely an H-bond donor, and 2-OH and 3-OH are donors and/or acceptors in network with each other, and with the EcR. The strategy of alkylation points the way to improved ecdysteroidal actuators for switch-activated gene therapy. | |
| 2009 PLoS ONE, 2009, 4, e6202 Regulation of the Drosophila Enhancer of split and invected-engrailed gene complexes by sister chromatid cohesion proteins. The cohesin protein complex was first recognized for holding sister chromatids together and ensuring proper chromosome segregation. Cohesin also regulates gene expression, but the mechanisms are unknown. Cohesin associates preferentially with active genes, and is generally absent from regions in which histone H3 is methylated by the Enhancer of zeste [E(z)] Polycomb group silencing protein. Here we show that transcription is hypersensitive to cohesin levels in two exceptional cases where cohesin and the E(z)-mediated histone methylation simultaneously coat the entire Enhancer of split and invected-engrailed gene complexes in cells derived from Drosophila central nervous system. These gene complexes are modestly transcribed, and produce seven of the twelve transcripts that increase the most with cohesin knockdown genome-wide. Cohesin mutations alter eye development in the same manner as increased Enhancer of split activity, suggesting that similar regulation occurs in vivo. We propose that cohesin helps restrain transcription of these gene complexes, and that deregulation of similarly cohesin-hypersensitive genes may underlie developmental deficits in Cornelia de Lange syndrome. | |
| 2009 Nature, 2009, 460, 405-409 The AP-1 transcription factor Batf controls T(H)17 differentiation. Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity. Here we show that Batf is required for the differentiation of IL17-producing T helper (T(H)17) cells. T(H)17 cells comprise a CD4(+) T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity. Batf(-/-) mice have normal T(H)1 and T(H)2 differentiation, but show a defect in T(H)17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf(-/-) T cells fail to induce known factors required for T(H)17 differentiation, such as RORgamma t (encoded by Rorc) and the cytokine IL21 (refs 14-17). Neither the addition of IL21 nor the overexpression of RORgamma t fully restores IL17 production in Batf(-/-) T cells. The Il17 promoter is BATF-responsive, and after T(H)17 differentiation, BATF binds conserved intergenic elements in the Il17a-Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in T(H)17 differentiation. | |
| 2008 J. Med. Chem., 2008, 51, 752-759 Coumarin as attractive casein kinase 2 (CK2) inhibitor scaffold: an integrate approach to elucidate the putative binding motif and explain structure-activity relationships. Casein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, we have synthetized and tested a small library of coumarins (more than 60), rationalizing the observed structure-activity relationship. Moreover, the most promising inhibitor, 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC), has been also crystallized in complex with CK2, and the experimental binding mode has been used to derive a linear interaction energy (LIE) model. |
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| = Scientific Bibliography | |
| Pierre Ducrot <pierre.ducrot@gmail.com> | |
| v1.0, 7-Mar-2015 | |
| :neo4j-version: 2.2.0 | |
| :author: Pierre Ducrot | |
| :twitter: ducrot_pierre | |
| :tags: science, publication | |
| == Domain | |
| Science and Research. | |
| Bibliography is by definition a graph. It is contains a tree of journals, volumes, issues and articles, and become a graph when authors publish several articles. Further addition of keywords or topics binds articles together add complexity to the graph. Hence, creating a hierarchy of keywords and topics introduces additional complexity which prevent easy data handling using standard SQL databases. For instance, target or gene classification, or keyword synonims or keyword hierarchy (e.g. medicinal chemistry is part of chemistry). | |
| The proposed network lets scientists handle journals, papers, authors and keywords they read, and suggests articles for reading and can be used to filter upcoming publications and make reading recommendations. It may also be used to identify key authors or articles on a specific topics, as we'll demonstrate here. | |
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<!-- User&#45;&gt;Group -->
<g id="edge2" class="edge"><title>User&#45;&gt;Group</title>
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<!-- Author -->
<g id="node4" class="node"><title>Author</title>
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<!-- User&#45;&gt;Author -->
<g id="edge3" class="edge"><title>User&#45;&gt;Author</title>
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</g>
<!-- Annotation&#45;&gt;Group -->
<g id="edge6" class="edge"><title>Annotation&#45;&gt;Group</title>
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<!-- Paper -->
<g id="node5" class="node"><title>Paper</title>
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<text text-anchor="middle" x="316" y="-120.9" font-family="Helvetica,sans-Serif" font-size="12.00" fill="White">:Paper</text>
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<!-- Author&#45;&gt;Paper -->
<g id="edge7" class="edge"><title>Author&#45;&gt;Paper</title>
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<!-- Paper&#45;&gt;Annotation -->
<g id="edge9" class="edge"><title>Paper&#45;&gt;Annotation</title>
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<!-- URL -->
<g id="node6" class="node"><title>URL</title>
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<!-- Paper&#45;&gt;URL -->
<g id="edge4" class="edge"><title>Paper&#45;&gt;URL</title>
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<text text-anchor="middle" x="392" y="-126" font-family="Times,serif" font-size="10.00" fill="#d01c8b">:hasLink</text>
</g>
<!-- Volume -->
<g id="node7" class="node"><title>Volume</title>
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<!-- Paper&#45;&gt;Volume -->
<g id="edge8" class="edge"><title>Paper&#45;&gt;Volume</title>
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[] | |
| == Setup | |
| The sample data set has been taken from PubMed (www.ncbi.nlm.nih.gov/pubmed) and parsed using workflow software such as Knime (https://www.knime.org) or Pipeline Pilot (http://www.3ds.com/products-services/biovia). For the purpose of this demo, only authors who published twice or more were kept. | |
| //hide | |
| //setup | |
| [source,cypher] | |
| ---- | |
| CREATE INDEX ON :Journal(Name); | |
| CREATE INDEX ON :Volume(Name); | |
| CREATE INDEX ON :Paper(Year); | |
| CREATE INDEX ON :Paper(Reference); | |
| CREATE INDEX ON :Annotation(Name); | |
| LOAD CSV WITH HEADERS FROM 'https://gist.githubusercontent.com/pducrot/6c3d995ab59656d75a93/raw/ec67b360844f69b3b2317cacee076a6df177449a/journals.txt' as line FIELDTERMINATOR '\t' MERGE (j:Journal {Name: line.Journal}) MERGE (v:Volume {Name: line.Volume}) MERGE (j) <-[:publishedIn]- (v); | |
| LOAD CSV WITH HEADERS FROM 'https://gist.githubusercontent.com/pducrot/6c3d995ab59656d75a93/raw/82324b76548d52636d421388559f717c681e6c29/papers.txt' as line FIELDTERMINATOR '\t' CREATE (:Paper { Year: line.Year, Reference: line.Reference, Title: line.Title, Summary: line.Summary}); | |
| LOAD CSV WITH HEADERS FROM 'https://gist.githubusercontent.com/pducrot/6c3d995ab59656d75a93/raw/ec67b360844f69b3b2317cacee076a6df177449a/journals.txt' as line FIELDTERMINATOR '\t' MATCH (p:Paper {Reference: line.Reference}), (v:Volume {Name: line.Volume}) MERGE (v) <-[:publishedIn]- (p); | |
| LOAD CSV WITH HEADERS FROM 'https://gist.githubusercontent.com/pducrot/6c3d995ab59656d75a93/raw/e4cb07a2de5a5b004e82df7ad2dcc48bd5b4c083/authors.txt' as line FIELDTERMINATOR '\t' MATCH (p:Paper {Reference: line.Reference}) MERGE (a:Author {Name: line.Author}) MERGE (a) -[:authored]-> (p); | |
| LOAD CSV WITH HEADERS FROM 'https://gist.githubusercontent.com/pducrot/6c3d995ab59656d75a93/raw/185b6a2ae2b9dfc77f1ad061e959d148d1ae6dc9/annotations.txt' as line FIELDTERMINATOR '\t' MATCH (p:Paper {Reference: line.Reference}) MERGE (a:Annotation {Name: line.Keyword}) MERGE (a) <-[:isRelatedTo]- (p); | |
| ---- | |
| [source,cypher] | |
| ---- | |
| MATCH path = (:Annotation {Name: "CoMFA"}) <-[:isRelatedTo*]- (p:Paper) <-[:authored]- (:Author), (p) -[:isRelatedTo]-> (:Annotation) | |
| RETURN path | |
| ---- | |
| //graph_result | |
| == Network at a glance | |
| [source,cypher] | |
| ---- | |
| MATCH (n) RETURN labels(n)[0] as NodeType, count(*) as Frequency | |
| ORDER BY NodeType ASC LIMIT 5 | |
| ---- | |
| //table | |
| [source,cypher] | |
| ---- | |
| MATCH (s) -[r]-> (t) | |
| RETURN labels(s)[0] as Source, count(distinct s) as nSources, | |
| type(r) as Relationship, count(r) as nRelationship, | |
| labels(t)[0] as Target, count(distinct t) as nTarget | |
| ---- | |
| //table | |
| == Useful queries | |
| === Get annotations and their frequency | |
| List all annotations and the number of papers they refere to. | |
| [source,cypher] | |
| ---- | |
| MATCH (a:Annotation)<-[:isRelatedTo]-(p:Paper) | |
| RETURN a.Name AS Keyword, count(p) as NumReferences | |
| ORDER BY NumReferences DESC | |
| LIMIT 5 | |
| ---- | |
| //table | |
| === Get papers | |
| Get all papers written by a specific author (e.g. "H. Matter"), report the Year of publication, reference and title. | |
| [source,cypher] | |
| ---- | |
| MATCH (a:Author {Name: "Matter H."}) -[:authored]-> (p:Paper) | |
| RETURN p.Year AS Year, p.Reference AS Reference, p.Title AS Title | |
| ORDER BY Year ASC, Reference ASC | |
| LIMIT 5 | |
| ---- | |
| //table | |
| === Get co-authors | |
| Get co-authors of papers written by a specific author (e.g. "H. Matter"), report the number of common papers and sort in descending order. | |
| [source,cypher] | |
| ---- | |
| MATCH (:Author {Name: "Matter H."}) -[:authored]-> (p:Paper) <-[:authored]- (a:Author) | |
| RETURN a.Name as CoAuthor, count(distinct p) AS NumCommonPapers | |
| ORDER BY NumCommonPapers DESC | |
| LIMIT 5 | |
| ---- | |
| //table | |
| === Paper annotation | |
| Add an annotation from a regular expression, matching in either the title or the summary. The annotation is storred into the graph as a new node which will hance contribute scorring upcoming papers or reading sugestions. Reports newly annotated papers afterwards. | |
| [source,cypher] | |
| ---- | |
| MATCH (p:Paper) | |
| WHERE p.Title =~ ".*\\bX-ray\\b.*" OR p.Summary =~ ".*\\bX-ray\\b.*" | |
| MERGE (a:Annotation {Name: "X-ray"}) | |
| MERGE (p) -[:isRelatedTo]-> (a) | |
| RETURN p.Reference as Reference, p.Title as Title, substring(p.Summary, 0, 50) as Summary | |
| LIMIT 5; | |
| ---- | |
| //table | |
| === Knowledge based annotations | |
| People in the field many annotate CoMFA as related to 3D-QSAR and 3D-QSAR as related to QSAR, itself related to molecular modeling, creating a hierarchy of annotations. Those would hence be very useful to score papers and suggest readings based on any annotation or just annotations related to a specific field of interest. | |
| //hide | |
| [source,cypher] | |
| ---- | |
| MATCH (a:Annotation {Name: "CoMFA"}), (b:Annotation {Name: "3D-QSAR"}) CREATE (a) -[:isRelatedTo]-> (b); | |
| MATCH (a:Annotation {Name: "CoMSIA"}), (b:Annotation {Name: "3D-QSAR"}) CREATE (a) -[:isRelatedTo]-> (b); | |
| MATCH (a:Annotation {Name: "3D-QSAR"}) MERGE (b:Annotation {Name: "QSAR"}) CREATE (a) -[:isRelatedTo]-> (b); | |
| MATCH (a:Annotation {Name: "QSAR"}) MERGE (b:Annotation {Name: "2D-QSAR"}) CREATE (a) <-[:isRelatedTo]- (b); | |
| MATCH (a:Annotation {Name: "QSAR"}) MERGE (b:Annotation {Name: "Molecular Modeling"}) CREATE (a) -[:isRelatedTo]-> (b); | |
| MATCH path = (:Annotation {Name: "QSAR"}) <-[:isRelatedTo*]- (p:Paper), (p) -[:isRelatedTo]-> (:Annotation) RETURN path | |
| ---- | |
| //graph_result | |
| === Reading suggestion | |
| In order to suggest reading, we need to either know what the scientist is currently reading - screen content - or have some knowledge about what he read and got interested in in the past. We chose the latter approach, linking annotations and imports to scientists. | |
| //hide | |
| [source,cypher] | |
| ---- | |
| MATCH (a:Annotation {Name: "CoMFA"}) MERGE (u:User {Name: "Pierre"}) CREATE (a) <-[:likes]- (u); | |
| MATCH (a:Annotation {Name: "CoMSIA"}) MERGE (u:User {Name: "Pierre"}) CREATE (a) <-[:likes]- (u); | |
| MATCH (a:Annotation {Name: "QSAR"}) MERGE (u:User {Name: "Pierre"}) CREATE (a) <-[:likes]- (u); | |
| MATCH (a:Annotation {Name: "PPAR"}) MERGE (u:User {Name: "Pierre"}) CREATE (a) <-[:likes]- (u); | |
| ---- | |
| Hence, sugeestions or scoring can be done either regardless or using specific topics of interest. For instance QSAR or even more restrictive CoMFA, which are modeling methods, or PPAR, which is a target/protein. Depending on the selected annotations, papers will score diffrently. | |
| === Author scoring | |
| Since we have authors, we may also score authors based on the field of interst and use their scores to impact on reading suggestions. One possibility is to use bayesian learning. From the data we get the probability of each annotation (keyword), p(K), the probability of authorship, p(A) and the probability of annotation given the author p(K|A), we can deduce p(A|K) = p(A)*p(K|A)/p(K) = Na / Nk where Na is the number of papers from a specific author annotated with keyword K and Nk is the number of papers annotated with K. However, because annotations are sampled different numbers of times, the error gets worse as Nk is lower. We can normalize the probability as follow: | |
| p'(A|K) = (Na + p(K)w) / (Nk + w) with w = 1/p(K) - Laplacian correction. Hence, p'(A|K) = (Na + 1) / (Nk + 1/p(K)). | |
| Na is obtained from [:authored] edges and can be stored into (:Author) nodes and further updated as follow: | |
| [source,cypher] | |
| ---- | |
| MATCH (a:Author) -[:authored]-> (p:Paper) | |
| WITH a, count(p) AS Na | |
| SET a.Na = Na | |
| RETURN a.Name, Na | |
| ORDER BY Na DESC | |
| LIMIT 5 | |
| ---- | |
| //table | |
| Smilarly, Nk is obtained from [:isRelatedTo] edges and can be stored into (:Annotation) nodes and further updated as follow: | |
| [source,cypher] | |
| ---- | |
| MATCH (:Annotation) <-[r:isRelatedTo]- (:Paper) | |
| WITH count(r) AS N | |
| MATCH (k:Annotation) <-[:isRelatedTo]- (p:Paper) | |
| WITH k, count(p) AS Nk, toFloat(count(p))/N as pK | |
| SET k.Nk = Nk, k.pK = pK | |
| RETURN k.Name, Nk, pK | |
| ORDER BY Nk DESC | |
| LIMIT 5 | |
| ---- | |
| //table | |
| With Na, Nk and pK stored, the scoring with cypher become easier: | |
| [source,cypher] | |
| ---- | |
| MATCH (k:Annotation) <-[:isRelatedTo]- (p:Paper) <-[:authored]- (a:Author) | |
| RETURN a.Name, k.Name, (toFloat(count(distinct p))+1)/(k.Nk + k.pK) as Score | |
| ORDER BY k.Name ASC, Score DESC | |
| LIMIT 5 | |
| ---- | |
| //table | |
| This query scored authors on topic relevance. With such a small data set, it may be difficult to evaluate the scoring, one may have a better idea by looking at the actual graph, and check that higly scored authors-keyword pairs occur when an author published several papers linked to the corresponding keyword. By specifying a keyword, we can retrieve the key authors, and even scoring on topic groups, such as "QSAR" having - in this example - no directly attached papers with [:isRelatedTo*] | |
| [source,cypher] | |
| ---- | |
| MATCH (k:Annotation {Name: "3D-QSAR"}) <-[:isRelatedTo]- (p:Paper) <-[:authored]- (a:Author) | |
| RETURN a.Name, k.Name, (toFloat(count(distinct p))+1)/(k.Nk + k.pK) as Score | |
| ORDER BY k.Name ASC, Score DESC | |
| LIMIT 5 | |
| ---- | |
| //table | |
| === Handle users or readers | |
| In order to provide a reader with proper suggestions, we need to introduce users in the graph, either as "interested in" a paper or "interested in" a keyword hence score keywords and authors through the user (reader). | |
| [source,cypher] | |
| ---- | |
| MATCH (k:Annotation {Name: "QSAR"}) | |
| MERGE (u:User {Name: "Pierre"}) | |
| MERGE (k) <-[:isInterestedIn]- (u); | |
| ---- | |
| === User / author relationship | |
| Readers usually publish papers as well, it therefore useful to link users to authors to identify the user's own papers. | |
| [source,cypher] | |
| ---- | |
| MATCH (a:Author {Name: "Matter H."}) | |
| MERGE (u:User {Name: "Hans"}) | |
| MERGE (u) -[:isAuthor]-> (a); | |
| MATCH path=(u:User {Name: "Hans"}) -[:isAuthor]-> (a:Author) -[:authored]-> (p:Paper) | |
| RETURN a.Name as Author, p.Reference as Reference | |
| LIMIT 5; | |
| ---- | |
| //table |
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