Steroidal aromatase inhibitors: Model receptor surfaces and 3D QSAR

Receptor surfaces have been generated with a training set of 50 steroids ac tive against cytochrome P450 enzyme, aromatase, using the Drug Discovery Wo rkbench (Cerius(2)). A combination of van der Waals-electrostatic and Wyvil l-partial-charge force fields together with overlay of 17- and 13-atoms of the steroid ligand resulted in four different receptor surface models. Thes e models have high conventional and cross-validated r(2), q(2) 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 analogue s are evaluated with receptor surfaces and their biological activity predic ted 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) c onformation 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.