HIV-reverse transcriptase inhibition: inclusion of ligand-induced fit by cross-docking studies

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), a definitive role in the treatment of HIV-1 infections. Since the appearance of HEPT and TIBO, more than 30 structurally different classes of compounds have been reported as NNRTIs, which are specific inhibitors of HIV-1 replication, targeting the HIV-1 reverse transcriptase (RT). Nevirapine and delavirdine are the first formally licensed for clinical use, and others have been licensed afterward, while several are in preclinical or clinical development. The NNRTIs interact with a specific site of HIV-1 RT (nonnucleoside binding site, NNBS) that is close to, but distinct from, the NRTI binding site. In this work we report the application of the Autodock program assessing its usability through reproduction of 41 NNRTI experimental bound conformations. Moreover, cross-docking experiments on the wild-type and mutated RT forms were conducted to take into account the enzyme flexibility as a valuable tool for structure-based drug design (SBDD) studies and to gain insight on the mode of action of new anti-HIV agents active against both wild-type and resistant strains.