Molecular docking and MM/GBSA integrated protocol for designing small molecule inhibitors against HIV-1 gp41

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• 作者：Ramakrishna Munnaluri (1)
  Sree Kanth Sivan (1)
  Vijjulatha Manga (1)
  
  1. Molecular Modeling and Medicinal Chemistry Group ; Department of Chemistry ; University College of Science ; Osmania University ; Hyderabad ; 500007 ; India
  
• 关键词：Glycoprotein 41 (gp41) ; Six ; helix bundle (6 ; HB) ; Extra precision (XP) docking ; Induced fit docking (IFD) ; QM ; polarized ligand docking (QPLD) ; Molecular mechanics/generalized born surface area (MM/GBSA)
• 刊名：Medicinal Chemistry Research
• 出版年：2015
• 出版时间：February 2015
• 年：2015
• 卷：24
• 期：2
• 页码：829-841
• 全文大小：8,423 KB
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• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
• 出版者：Springer US
• ISSN：1554-8120

文摘

Human immunodeficiency virus type-1 (HIV-1) enters into the host cell using its non-covalently bonded envelope glycoproteins 120 and 41 (gp120 and gp41). HIV-1 gp41 plays an instrumental role in the membrane fusion and entry of viral genome into the host cytosol. Binding of virus to host cell receptors triggers a cascade of conformational changes in gp120 and gp41. During the fusion, core of gp41 comprising C-heptad repeat coils into the highly conserved, deep hydrophobic pocket of N-heptad repeat forming a six-helix bundle (6-HB). The apposition of the host cell membrane and viral membrane is initiated with the formation of 6-HB. The inhibition of 6-HB formation has been proved to be an effective way to thwart the viral and host cell fusion. In this work, we have performed computational study on 62 6-HB formation inhibitors reported in the literature. An integrated computational protocol using molecular docking and molecular mechanics/generalized born surface area calculations was employed to these known inhibitors to understand mode of interaction with receptor. Our study revealed reasonably good agreement between computational parameters and experimental inhibitory potentials of these molecules. The results encouraged us to design novel gp41 6-HB formation inhibitors.