Affinity and selectivity of matrix metalloproteinase inhibitors: A chemometrical study from the perspective of ligands and proteins

A novel strategy to understand affinity and selectivity for enzyme inhibito rs using information from ligands and target protein 3D structures is descr ibed. It was applied to 2-arylsulfonyl-1,2,3,4-tetrahydro-isoquinoline-3-ca rboxylates and -hydroxamates as inhibitors of the matrix metalloproteinases MMP-3 (stromelysin-l) and MMP-8 (human neutrophil collagenase). As the fir st step, consistent and predictive 3D-QSAR models were derived using CoMFA, CoMSIA, and GRID/Golpe approaches, leading to the identification of bindin g regions where steric, electronic, or hydrophobic effects are important fo r affinity. These models were validated using multiple analyses using two o r five randomly chosen cross-validation groups and randomizations of biolog ical activities. Second, 3D-QSAR models were derived based on the affinity ratio IC50-(MMP-8)/IC50(MMP-3), allowing the identification of key ligand d eterminants for selectivity toward one of both enzymes. In addition to this ligands' view, the third step encompasses a chemometrical approach based a n principal component analysis (PCA) of multivariate GRID descriptors to un cover the major differences between both protein binding sites with respect to their GRID probe interaction pattern. The resulting information, based on the accurate knowledge of the target protein 3D structures, led to a con sistent picture in good agreement with experimentally observed differences in selectivity toward MMP-8 or MMP-3. The interpretation of all three class es of statistical models leads to detailed SAR information for MMP inhibito rs, which is in agreement with available data for binding site topologies, ligand affinities, and selectivities. Thus the combined chemical analyses p rovide guidelines and accurate activity predictions for designing novel, se lective MMP inhibitors.