Predicting anti-HIV activity of 1,1,3-trioxo[1,2,4]-thiadiazine (TTD) derivatives: 3D QSAR approach

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Human immunodeficiency virus type 1 (HIV-1) is the pathogenic retrovirus and causative agent of acquired immunodeficiency syndrome (AIDS). HIV-1 reverse transcriptase (RT) is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and nucleoside reverse-transcriptase inhibitors (NRTIs). NNRTIs bind in a region not associated with the active site of the enzyme. Within the NNRTIs category, there is a set of inhibitors commonly referred to as 1,1,3-trioxo-thiadiazine (TTD) derivatives. Based on the structures and biodata of previous TDS analogs, three-dimensional (3D) quantitative structure–activity relationship (QSAR) studies have been performed which resulted in two reliable computational models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) with r 2 values of 0.883 and 0.852 and q 2 values of 0.639 and 0.608, respectively. The predictive ability of the developed CoMFA and CoMSIA models was also confirmed by using a test (external validation) set comprised of eight molecules, with predicted r 2 value of 0.832 and 0.760, respectively. It is shown that the steric and electrostatic properties predicted by CoMFA contours and hydrophobic properties predicted by CoMSIA contours can be related to anti-HIV activity. These models are a significant guide to trace the features that really matter, especially with respect to design of novel compounds. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of 1,1,3-trioxo-thiadiazine (TTDs) derivatives. The parameters indicated are responsible for increasing anti-HIV activity.