title: Molecular dynamics and Monte Carlo simulations for protein-ligand binding and inhibitor design.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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".
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cole
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Tirado-Rives
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA. Electronic address: william.jorgensen@yale.edu.
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001583:Benzoxazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017076:Computer-Aided Design; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics; D004735:Energy Transfer; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009010:Monte Carlo Method; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D001583:Benzoxazoles; D008024:Ligands; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Enhanced sampling; Free energy perturbation; Non-nucleoside inhibitors of HIV-1 reverse transcriptase; Replica exchange with solute tempering