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

The human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is still one of the most attractive targets in the design of new antiviral agents. It is a key enzyme for viral replication which has two associated catalytic functions: a DNA polymerase activity and a ribonuclease H (RNase H) activity. Even though there are several known inhibitors of the RT-associated DNA polymerase function, only few inhibitors of its RNase H function have been identified so far. Here, we report the first application of virtual screening (VS) methods for discovering new inhibitors of this novel and challenging target. The overall VS campaign consisted of two consecutive screening processes, each of it resulting in a hit list of compounds which were tested experimentally. Firstly, the virtual screening platform ROCS (Rapid Overlay of Chemical Structures) was utilized to perform in silico shape-based similarity screening in which an hydrazone derivative, previously shown to inhibit the HIV-1 RNase H, was chosen as a query. Consequently, the most active molecules identified in the first VS were selected as queries for a parallel VS which combined three different LB methods: shape-based, 2D-fingerprint, 3D-pharmacophore VS. The effect of the VS selected molecules on the HIV-1 RT-associated activities were evaluated in biochemical assays. Overall, a set of molecules characterized by different scaffolds were identified as new inhibitors of both RT-associated activities in the micromolar range.