Linking CoMFA and protein homology models of enzyme-inhibitor interactions: an application to non-steroidal aromatase inhibitors

An approach to compare quantitatively a ligand-based (CoMFA) model and an e nzyme active site model was investigated. The active site of the cytochrome P450 human aromatase was constructed by homology modeling techniques and t wo structurally different non-steroidal aromatase inhibitors were docked in to it. A CoMFA model was then developed on a related series of non-steroida l inhibitors by correlating their inhibitory activity (expressed as -log IC 50 values) versus only 11 steric descriptors (i.e. C-sp3-ligand steric inte raction energies). The resulting 3D-QSAR coefficients (II) and the steric f ield values of the aromatase active site calculated at the same points of t he CoMFA lattice (i.e. eleven C-sp3-protein steric interaction energies) we re pair-wise compared. Specifically, when a positive coefficient was associ ated with a negative or low (< 5 kcal/mol) value of the protein steric fiel d or, alternatively, a negative coefficient was associated with a large pos itive value of the protein steric field we recorded as many matches. When a 3D-QSAR coefficient did not correspond to the protein steric potential in the sense described above we considered that point as a mis-matching point. In our view, in spite of several limitations, such a comparison represents a valuable criterion to evaluate quantitatively how convergent are the res ults from a 3D-QSAR CoMFA model and a homology-built protein 3D structure. (C) 2000 Elsevier Science Ltd. All rights reserved.