Computational studies of the binding mode and 3D-QSAR analyses of symmetric formimidoester disulfides: a new class of non-nucleoside HIV-1 reverse transcriptase inhibitor.

Abstract  Symmetric formimidoester disulfides (DSs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Given that three geometric isomers for DSs are possible, a computational strategy based on molecular docking studies, followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was used in order to identify the most probable DS isomer interacting with RT, to elucidate the atomic details of the RT/DS interaction, and to identify key features impacting DS antiretroviral activity. The CoMFA model was found to be the more predictive, with values of $${\text{r}}_{{\text{ncv}}}^{\text{2}} = {\text{0}}{\text{.95}}$$, $${\text{r}}_{{\text{cv}}}^{\text{2}} = {\text{0}}{\text{.482}}$$, SEE = 0.264, F = 80, and $${\text{r}}_{{\text{pred}}}^{\text{2}} = {\text{0}}{\text{.73}}$$. Figure Selected docking pose of the E,Z isomer of compound 15into the NNIBS [non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) binding site]. The RT surface electrostatic distribution (Connolly surface) is shown. Green areas are related to hydrophobic region while magenta areas indicate for H-bond regions [ABSTRACT FROM AUTHOR]