Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis

A set of 90 novel 2-(arylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxy lates 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. Dockin g studies of a reference compound are based on crystal structures of MMP-8 complexed with peptidic inhibitors to propose a model of its bioactive conf ormation. This model was validated by a 1.7 Angstrom X-ray structure of the catalytic domain of MMP-8. The 3D-QSAR models based on a superposition rul e derived from these docking studies were validated using conventional and cross-validated r(2) values using the leave-one-out method, repeated analys es 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 complementarit y. Subsets selected as smaller training sets using 2D fingerprints and maxi mum dissimilarity methods resulted in 3D-QSAR models with remarkable correl ation coefficients and a high predictive power. This allowed to compensate the weaker zinc binding properties of carboxylates by introducing optimal f itting P1' residues. The final QSAR information agrees with all experimenta l data for the binding topology and thus provides clear guidelines and accu rate activity predictions for novel MMP-8 inhibitors.