Quantitative Structure−Activity Relationship of Human Neutrophil Collagenase (MMP-8) Inhibitors Using Comparative Molecular Field Analysis and X-ray Structure Analysis
| Autor: | Hans Matter, Herman Schreuder, Haase Burkhard, Manfred Schudok, Günter Dr. Billen, Denis Barbier, Werner Thorwart, Klaus Ulrich Dr Weithmann, Bernhard Neises, Volker Brachvogel, Petra Lönze, Wilfried Schwab |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Steric effects Quantitative structure–activity relationship Structure analysis Human neutrophil Protein Conformation Chemistry Stereochemistry Crystal structure Matrix Metalloproteinase Inhibitors Matrix metalloproteinase Crystallography X-Ray Structure-Activity Relationship Matrix Metalloproteinase 8 Docking (molecular) Drug Design Drug Discovery Collagenase medicine Humans Molecular Medicine Protease Inhibitors Collagenases medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 42:1908-1920 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm980631s |
| Popis: | A set of 90 novel 2-(arylsulfonyl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxylates and -hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) was designed, synthesized, and investigated by 3D-QSAR techniques (CoMFA, CoMSIA) and X-ray structure analysis. Docking studies of a reference compound are based on crystal structures of MMP-8 complexed with peptidic inhibitors to propose a model of its bioactive conformation. This model was validated by a 1. 7 A X-ray structure of the catalytic domain of MMP-8. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r2 values using the leave-one-out method, 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 MMP-8 catalytic 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. This allowed to compensate the weaker zinc binding properties of carboxylates by introducing optimal fitting P1' residues. The final QSAR information agrees with all experimental data for the binding topology and thus provides clear guidelines and accurate activity predictions for novel MMP-8 inhibitors. |
| Databáze: | OpenAIRE |
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