Molecular dynamics and Monte Carlo simulations for protein–ligand binding and inhibitor design

• Published in: Biochimica et biophysica acta Vol. 1850; no. 5; pp. 966 - 971
• Main Authors: Cole, Daniel J., Tirado-Rives, Julian, Jorgensen, William L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2015
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Benzoxazoles - chemistry; Benzoxazoles - metabolism; Benzoxazoles - pharmacology; Computer-Aided Design; Drug Design; Drug Resistance, Viral - genetics; energy; Energy Transfer; Enhanced sampling; Free energy perturbation; Gibbs free energy; HIV infections; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; Human immunodeficiency virus; Hydrophobic and Hydrophilic Interactions; hydrophobicity; Ligands; molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Monte Carlo Method; Mutation; Non-nucleoside inhibitors of HIV-1 reverse transcriptase; Protein Binding; Protein Conformation; Replica exchange with solute tempering; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - metabolism; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; Structure-Activity Relationship; Replica exchange with solute tempering; Free energy perturbation; Non-nucleoside inhibitors of HIV-1 reverse transcriptase; Enhanced sampling
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.08.018

Non-nucleoside inhibitors of HIV reverse transcriptase are an important component of treatment against HIV infection. Novel inhibitors are sought that increase potency against variants that contain the Tyr181Cys mutation. Molecular dynamics based free energy perturbation simulations have been run to study factors that contribute to protein–ligand binding, and the results are compared with those from previous Monte Carlo based simulations and activity data. Predictions of protein–ligand binding modes are very consistent for the two simulation methods; the accord is attributed to the use of an enhanced sampling protocol. The Tyr181Cys binding pocket supports large, hydrophobic substituents, which is in good agreement with experiment. Although some discrepancies exist between the results of the two simulation methods and experiment, free energy perturbation simulations can be used to rapidly test small molecules for gains in binding affinity. Free energy perturbation methods show promise in providing fast, reliable and accurate data that can be used to complement experiment in lead optimization projects. This article is part of a Special Issue entitled “Recent developments of molecular dynamics”. [Display omitted] •Novel non-nucleoside inhibitors of HIV reverse transcriptase are sought.•Free energy perturbation simulations are compared with activity data.•Enhanced sampling improves consistency of theoretical results.•Hydrophobic substituents improve potency against the Tyr181Cys mutant.•Simulations provide fast, reliable and accurate predictions.