Three-dimensional quantitative structure-activity relationships study on HIV-1 reverse transcriptase inhibitors in...

A three-dimensional quantitative structure-activity relationships (3D QSAR) method, Comparative Molecular Field Analysis (CoMFA), was applied to a set of dipyridodiazepinone (nevirapine) derivatives active against wild-type (WT) and mutant-type (Y181C) HIV-1 reverse transcriptase. The starting geometry of dipyridodiazepinone was taken from X-ray crystallographic data. All 75 derivatives, divided into a training set of 53 compounds and a test set of 22 molecules, were then constructed and full geometrical optimizations were performed, based on a semiempirical molecular orbital method (AM1). CoMFA was used to discriminate between structural requirements for WT and Y181C inhibitory activities. The resulting CoMFA models yield satisfactory predictive ability regarding WT and Y181C inhibitions, with r2 cv = 0.624 and 0.726, respectively. CoMFA contour maps reveal that steric and electrostatic interactions corresponding to the WT inhibition amount to 58.5% and 41.5%, respectively, while steric and electrostatic effects have approximately equal contributions for the explanation of inhibitory activities against Y181C. The contour maps high-light different characteristics for different types of wild-type and mutant-type HIV-1 RT. In addition, these contour maps agree with experimental data for the binding topology. Consequently, the results obtained provide information for a better understanding of the inhibitor-receptor interactions of dipyridodiazepinone analogs.