Steroidal aromatase inhibitors : Model receptor surfaces and 3 D QSAR

Receptor surfaces have been generated with a training set of 50 steroids active against cytochrome P450 enzyme, aromatase, using the Drug Discovery Workbench (Ceriui). A combination of van der Waals-electrostatic and Wyvill­ partial-charge force fields together with overlay of 17and 1 3-atoms of the steroid ligand resulted in four different receptor surface models. These models have high conventional and cross-validated ?, q2 values (> 0.8) for 50 training set molecules with the four components, vdW-17A, vdW-1 3A, 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 ( I ) van der Waals vs. Wyvill force fields, (2) 17vs. 1 3-atoms overlay, (3) conformation of the 2-oxasteroid. Our computations show that replacement of C2-methylene group with an a-atom in the A-ring of androgens (2-oxasteroids) is accommodated during recognition by the receptor.