In this work we report a parallel application of both docking-and shape-based virtual screening (VS) methods, followed by Molecular Dynamics simulations (MDs), for discovering new compounds able to inhibit the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) RNA-dependent DNA polymerase activity. Specifically, we screened more than 143000 natural compounds commercially available in the ZINC database against the best five RT crystallographic models, taking into account the five approved NNRTIs as query compounds. As a result, 20 hit molecules were selected and tested on biochemical assays for the inhibition of the RNA dependent DNA polymerase RT function and, among them, an indoline pyrrolidine (hit 1), an indonyl piperazine (hit 2) and an indolyl indolinone (hit 3) derivatives were identified as novel non-nucleoside RT inhibitors in the low micromolar range. KEYWORDS: Reverse transcriptase; NNRTIs; in silico virtual screening; natural products.
EXPERIMENTAL SECTIONActive compounds. The active compounds used in this study were obtained from the ChEMBL database. 48 We firstly indicated the HIV-1 reverse transcriptase as target and then selected, from various literature sources, 50 molecules with IC 50 values lower than 20 nM. Moreover, in the active set we included also the five approved NNRTIs, that are delavirdine, efavirenz, nevirapine, etravirine and rilpivirine, thus globally obtaining 55 molecules. In Table S3, the ChEMBL code, the SMILES chemical formula 49 and the IC 50 values of the active