Two- and three-dimensional QSAR studies on benzyl amide-ketoacid inhibitors of HIV integrase and their reduced analogues

Abstract

The discovery of clinically relevant inhibitors of HIV-integrase for antiviral therapy has proven to be a challenging task. Ketoacid-derived inhibitors selectively inhibit the strand transfer reaction of HIV-integrase. To elucidate the structural properties required for HIV-integrase inhibitory activity, we present here the results of two- and three-dimensional (2D and 3D) QSAR studies of a series of 24 benzyl amide derivatives. The 2D-QSAR studies were performed using three methods: the multiple linear regression method (MLR), giving r 2 = 0.9340 and q 2 = 0.8471; the partial least squares method, with r 2 = 0.9291 and q 2 = 0.7896; and principle component analysis, giving r 2 = 0.6496 and q 2 = 0.3893. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest-neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient (q 2) of 0.4577 and a non-cross-validated correlation coefficient (r 2) of 0.5836 were obtained. Contour maps using this approach showed that steric effects dominantly determine binding affinities. The information rendered by 2D and 3D QSAR models may lead to a better understanding of structural requirements of HIV-integrase inhibitors and can help in the design of novel potent molecules.