Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes

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• 作者：Richard A. Friesner ; Robert B. Murphy ; Matthew P. Repasky ; Leah L. Frye ; Jeremy R. Greenwood ; Thomas A. Halgren ; Paul C. Sanschagrin ; Daniel T. Mainz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：October 19, 2006
• 年：2006
• 卷：49
• 期：21
• 页码：6177 - 6196
• 全文大小：799K
• 年卷期：v.49,no.21(October 19, 2006)
• ISSN：1520-4804

文摘

A novel scoring function to estimate protein-ligand binding affinities has been developed and implementedas the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energyterms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobicenclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic proteinatoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment,and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocolhave been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments fora set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of thenovel XP molecular recognition and water scoring in separating active and inactive ligands and avoidingfalse positives.