Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 45, Issue 1, Pages 227-235Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2009.09.048
Keywords
Molecular dynamics simulation; MM-PBSA; HIV-1 protease; Drug resistance
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Funding
- National Nature Science Foundation of China [10874104, 10474060, 10504017]
- Ministry of Education [206093]
- Nature Science Foundation of Shandong Province [Z2007A05]
- Shandong Province Foundation [2008BS01013]
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The single mutations I50V, V82A and I84V are considered as the key residue mutations of the HIV-1 protease drug resistance. The rank of calculated absolute binding free energies using MM-PBSA method is in excellent agreement with experimental result. Enthalpic and entropic balance is analyzed to explain resistance in I50V and V82A having a higher entropic contribution than in the wild type (WT) complex. The reduced van der Waals energy explains the drug resistance of I84V to GRL-98065. Detailed binding free energies between GRL-98065 and individual protein residues are calculated to provide insights into the inhibitor-protein binding and drug-resistant mechanism. Our results show I50V and V82A have larger structural changes than I84V compared with WT. (C) 2009 Elsevier Masson SAS. All rights reserved.
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