Steroidal aromatase inhibitors : Model receptor surfaces and 3D QSAR^†

Abstract

1054-1062Receptor surfaces have been generated with a training set of 50 steroids active against cytochrome P450 enzyme, aromatase, using the Drug Discovery Workbench (Cerius2). A combination of van der Waals-electrostatic and Wyvill-partial- charge force fields together with overlay of 17- and 13-atoms of the steroid ligand resulted in four different receptor surface models. These models have high conventional and cross-validated r2, q2 values (> 0.8) for 50 training set molecules with the four components, vdW-17A, vdW-13A, Wsc-17A, Wsc-13A. Binding energies of six synthetic 2-oxasteroid analogues are evaluated with receptor surfaces and their biological activity predicted through 3D QSAR. Ligand-receptor binding is examined in relation to (1) van der Waals vs. Wyvill force fields, (2) 17- vs. 13-atoms overlay, (3) conformation of the 2-oxasteroid. Our computations show that replacement of C2-methylene group with an O-atom in the A-ring of androgens (2-oxasteroids) is accommodated during recognition by the receptor