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.