Design of nevirapine derivatives insensitive to the K103N and Y181C HIV-1 reverse transcriptase mutants

Abstract

Nevirapine (Viramune®) belongs to the first generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Its efficiency is limited by drug resistant mutations, such as K103N and Y181C, so, the aim of this work was to design novel nevirapine analogues insensitive to the K103N and Y181C HIV-1 RT. 360 Nevirapine derivatives were designed using a combinatorial library design approach and these compounds were docked into the binding pocket of mutant HIV-1 RT enzyme structures, using the GOLD program. 124 Compounds having a GoldScore higher than that of nevirapine (55.00 and 52.00 for K103N and Y181C mutants, respectively) were first retrieved and submitted to a topological analysis with the SILVER program. Consequently, 31 compounds presenting a significant percentage of the surfaces buried upon binding (>80%) and exhibiting hydrogen bonds to either N103 or C181 residues of the HIV-RT were selected. To ensure that these compounds had hydrogen bonding interaction to either N103 or C181 residues, their interaction energies were estimated by quantum chemical calculations (QCCs). Finally, QCCs represent an alternative method for performing post docking procedure.

†Presented at CMTPI 2005: Computational Methods in Toxicology and Pharmacology Integrating Internet resources (Shanghai, China, October 29–November 1 2005).

Keywords:

• NNRTIs
• HIV-1 RT
• K103N
• Y181C
• Combinatorial library design
• Quantum chemical calculations

Acknowledgements

This investigation was supported by the Thailand Research Fund (BRG4780007). P.S. is grateful to the Royal Golden Jubilee Ph.D. program (3.C.KU/45/B.1) and the French Embassy in Thailand for scholarships. Laboratory for Computational and Applied Chemistry (LCAC), the Postgraduate program in education and research on Petroleum and Petrochemical Technology (ADB-MUA), HPCC/NECTEC and Bioinformatics Research Group, Laboratoire de Pharmacochimie de la Communication Cellulaire are also gratefully acknowledged for research facilities and computing resources.

Notes

†Presented at CMTPI 2005: Computational Methods in Toxicology and Pharmacology Integrating Internet resources (Shanghai, China, October 29–November 1 2005).