1bzs

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Revision as of 14:09, 12 November 2007

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spinqualitylabelsall models 1bzs, resolution 1.7Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF MMP8 COMPLEXED WITH HMR2909

Overview

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.

About this Structure

1BZS is a Single protein structure of sequence from Homo sapiens with CA, ZN, BSI and EPE as ligands. Active as Neutrophil collagenase, with EC number 3.4.24.34 Full crystallographic information is available from OCA.

Reference

Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis., Matter H, Schwab W, Barbier D, Billen G, Haase B, Neises B, Schudok M, Thorwart W, Schreuder H, Brachvogel V, Lonze P, Weithmann KU, J Med Chem. 1999 Jun 3;42(11):1908-20. PMID:10354399

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