Comparison of Ligand-Based and Receptor-Based Virtual Screening of HIV Entry Inhibitors for the CXCR4 and CCR5 Receptors Using 3D Ligand Shape Matching and Ligand-Receptor Docking

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• 作者：Violeta I. P&eacute ; rez-Nueno ; David W. Ritchie ; Obdulia Rabal ; Rosalia Pascual ; Jose I. Borrell ; Jordi Teixidó
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2008
• 出版时间：March 2008
• 年：2008
• 卷：48
• 期：3
• 页码：509 - 533
• 全文大小：1814K
• 年卷期：v.48,no.3(March 2008)
• ISSN：1549-960X

文摘

HIV infection is initiated by fusion of the virus with the target cell through binding of the viral gp120protein with the CD4 cell surface receptor protein and the CXCR4 or CCR5 co-receptors. There is currentlyconsiderable interest in developing novel ligands that can modulate the conformations of these co-receptorsand, hence, ultimately block virus-cell fusion. This article describes a detailed comparison of the performanceof receptor-based and ligand-based virtual screening approaches to find CXCR4 and CCR5 antagonists thatcould potentially serve as HIV entry inhibitors. Because no crystal structures for these proteins are available,homology models of CXCR4 and CCR5 have been built, using bovine rhodopsin as the template. For ligand-based virtual screening, several shape-based and property-based molecular comparison approaches havebeen compared, using high-affinity ligands as query molecules. These methods were compared by virtuallyscreening a library assembled by us, consisting of 602 known CXCR4 and CCR5 inhibitors and some 4700similar presumed inactive molecules. For each receptor, the library was queried using known binders, andthe enrichment factors and diversity of the resulting virtual hit lists were analyzed. Overall, ligand-basedshape-matching searches yielded higher enrichments than receptor-based docking, especially for CXCR4.The results obtained for CCR5 suggest the possibility that different active scaffolds bind in different wayswithin the CCR5 pocket.