Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a novel class of piperazine-based stromelysin-1 (MMP-3) inhibitors: Applying a "divide and conquer" strategy

Three-dimensional quantitative structure-activity relationship (3D-QSAR) mo dels have been obtained using comparative molecular field analysis (CoMFA) for a novel series of piperazine-based matrix metalloproteinase inhibitors (MMPIs). The crystal structure of stromelysin-1 (MMP-3) was used to identif y regions of the enzyme and inhibitors where steric and electrostatic effec ts correlate strongly with biological activity. A training set composed of a subset of inhibitors (#10-35), which differed only with regards to the su bstituent (n-alkyl, amide, carbamide and sulfonamide) on the piperazine dis tal nitrogen, yielded the most predictive CoMFA model, with r(2) values of 0.592 (cross-validated) and 0.989 (conventional); this model was further va lidated using test compounds from two inhibitor subsets. Investigation of v arious ligand conformations, inhibitor subsets, alignment schemes and parti al charge formalisms was required to obtain satisfactory models. The greate st success was achieved by incorporating inertial alignment together with m anual adjustment of the enzyme-docked inhibitors to ensure complementarity between the inhibitors' substituent conformations and the structural charac teristics of the MMP-3 S1-S2' binding pockets. Key insights into the struct ure-activity relationship (SAR) obtained from this analysis for this inhibi tor set are in agreement with experimentally observed data on stromelysin-1 biological activity and binding-site topology. In particular, the present study sheds new light on the steric and electrostatic requirements for liga nd binding to the partly solvent-exposed S1-S2' area.