A Comparative Molecular Dynamics, MM鈥揚BSA and Thermodynamic Integration Study of Saquinavir Complexes with Wild-Type HIV-1 PR and L10I, G48V, L63P, A71V, G73S, V82A and I84V Single Mutants

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• 作者：Haralambos Tzoupis ; Georgios Leonis ; Thomas Mavromoustakos ; Manthos G. Papadopoulos
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2013
• 出版时间：March 12, 2013
• 年：2013
• 卷：9
• 期：3
• 页码：1754-1764
• 全文大小：588K
• 年卷期：v.9,no.3(March 12, 2013)
• ISSN：1549-9626

文摘

A great challenge toward Acquired Immunodeficiency Syndrome (AIDS) treatment is to combat the HIV-1 virus. The major problem of drug resistance has kept the virus one step ahead of the medical community, and the call for more effective drugs remains as urgent as ever. Saquinavir, the first inhibitor against HIV-1 protease, offers the most extensive clinical data regarding resistance mutations. In this work, we examine L10I, G48V, L63P, A71V, G73S, V82A, and I84V single mutant HIV-1 PR strains in complexes with saquinavir to elucidate drug鈥損rotease interactions and dynamics. A comparative analysis of these mutations at the molecular level may lead to a deeper understanding of saquinavir resistance. The G48V mutation induces structural changes to the protease that reflect upon the drug鈥檚 binding affinity, as shown by MM鈥揚BSA and thermodynamic integration (TI) calculations (螖螖G_TI = 0.3 kcal/mol; 螖螖G_MM鈥揚BSA = 1.2 kcal/mol). It was shown that mutations, which increase the flexibility of the flaps (G48V, L63P, L10I) diminish binding. The preservation of hydrogen bonds of saquinavir with both the active site and flap residues in the wild-type and certain single mutants (A71V, V82A) is also crucial for effective inhibition. It was shown that mutations conferring major resistance (G48V, L63P, I84V) did not present these interactions. Finally, it was indicated that a water-mediated hydrogen bond between saquinavir and Asp29 in the active site (wild-type, A71V, G73S) facilitates a proper placement of the drug into the binding cavity that favors binding. Mutants lacking this interaction (G48V, V82A, I84V) demonstrated reduced binding affinities. This systematic and comparative study is a contribution to the elucidation of the drug resistance mechanism in HIV-1 PR.