Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophore-based virtual screening approach

We report the first application of ligand-based virtual screening (VS) methods for discovering new compounds able to inhibit both human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT)-associated functions, DNA polymerase and ribonuclease H (RNase H) activities. The overall VS campaign consisted of two consecutive screening processes. In the first, the VS platform Rapid Overlay of Chemical Structures (ROCS) was used to perform in silico shape-based similarity screening on the NCI compounds database in which a hydrazone derivative, previously shown to inhibit the HIV-1 RT, was chosen. As a result, 34 hit molecules were selected and assayed on both RT-associated functions. In the second, the 4 most potent RT inhibitors identified were selected as queries for parallel VS performed by combining shape-based, 2D-fingerprint and 3D-pharmacophore VS methods. Overall, a set of molecules characterized by new different scaffolds were identified as novel inhibitors of both HIV-1 RT-associated activities in the low micromolar range.

Graphical abstractA combination of two consecutive virtual screening processes led to the discovery of dual inhibitors of reverse transcriptase associated functions, DNA polymerase and ribonuclease H (RNase H) activities.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We applied 2 successive virtual screening methods to identify new HIV-1 RT inhibitors. ► Molecules with different scaffolds inhibited both HIV-1 RT-associated functions. ► The most potent hit inhibited both HIV-1 RT functions at 1–2 μM concentration. ► This is the first RT inhibitor which inhibits both RT function in the low μM range.