title: Comparison of the molecular dynamics and calculated binding free energies for nine FDA-approved HIV-1 PR drugs against subtype B and C-SA HIV PR.
abstract: We report the first account of a comparative analysis of the binding affinities of nine FDA-approved drugs against subtype B as well as the South African subtype C HIV PR (C-SA). A standardized protocol was used to generate the inhibitor/C-SA PR complexes with the relative positions of the inhibitors taken from the corresponding X-ray structures for subtype B complexes. The dynamics and stability of these complexes were investigated using molecular dynamics calculations. Average relative binding free energies for these inhibitors were calculated from the molecular dynamics simulation using the molecular mechanics generalized Born surface area method. The calculated energies followed a similar trend to the reported experimental binding free energies. Postdynamic hydrogen bonding and electrostatic interaction analysis of the inhibitors with both subtypes reveal similar interactions. Most inhibitors show slightly weaker binding affinities for C-SA PR. Molecular dynamics studies demonstrated increased flap movement for C-SA PR, which can perhaps explain the weaker affinities. This study serves as a standardized platform for optimizing the design of future more potent HIV C-SA PR inhibitors.
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa.
authors.forename: Shaimaa M
authors.initials: SM
authors.lastname: Ahmed
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
authors.forename: Thirumala
authors.initials: T
authors.lastname: Govender
authors.forename: Glenn E M
authors.initials: GE
authors.lastname: Maguire
authors.forename: Yasien
authors.initials: Y
authors.lastname: Sayed
authors.forename: Mahmoud A A
authors.initials: MA
authors.lastname: Ibrahim
authors.forename: Previn
authors.initials: P
authors.lastname: Naicker
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013816:Thermodynamics; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1