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- Title
Systematic protein-protein docking and molecular dynamics studies of HIV-1 gpl20 and CD4: insights for new drug development.
- Authors
Chong Teoh T.; Heidelberg T.; Rizman-Idid M.
- Abstract
Background and the purpose of the study: The interactions between HIV-1 gpl20 and mutated CD4 proteins were investigated in order to identify a lead structure for therapy based on competitive blocking of the HIV binding receptor for human T-cells. Crystal structures of HIV gpl20-CD4 complexes reveal a close interaction of the virus receptor with CD4 Phe43, which is embedded in a pocket of the virus protein. Methods: This study applies computer simulations to determine the best binding of amino acid 43 CD4 mutants to HIV gpl20. Besides natural CD4, three mutants carrying alternate aromatic residues His, Trp and Tyr at position 43 were investigated. Several docking programs, were applied on isolated proteins based on selected crystal structures of gpl20-CD4 complexes, as well as a 5 ns molecular dynamics study on the protein complexes. The initial structures were minimized in Gromacs to avoid crystal packing effects, and then subjected to docking experiments using AutoDock4, FireDock, ClusPro and ZDock. In molecular dynamics, the Gibbs free binding energy was calculated for the gpl20-CD4 complexes. The docking outputs were analyzed on energy within the respective docking software. Results and conclusion: Visualization and hydrogen bonding analysis were performed using the Swiss-PdbViewer. Strong binding to HIV gpl20 can be achieved with an extended aromatic group (Trp). However, the sterical demand of the interaction affects the binding kinetics. In conclusion, a ligand for an efficient blocking of HIV gpl20 should involve an extended but conformational flexible aromatic group, i.e. a biphenyl. A docking study on biphenylalanine-43 confirms this expectation.
- Subjects
PHARMACEUTICAL chemistry; MOLECULAR biology methodology; HIV; MEMBRANE proteins; RESEARCH funding; CD4 antigen; DRUG development
- Publication
DARU: Journal of Pharmaceutical Sciences, 2011, Vol 19, Issue 6, p469
- ISSN
1560-8115
- Publication type
Article