Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes
Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes
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DOI：
10.1021/jm051256o
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发表时间：
2006-10-19
影响因子：
7.3
通讯作者：
Mainz, Daniel T.
中科院分区：
文献类型：
--
作者：
Friesner, Richard A.;Murphy, Robert B.;Mainz, Daniel T.
一种新的评估蛋白质-配体结合亲和力的评分功能已经被开发并实现为Glide 4.0 XP评分功能和对接协议。除了独特的水去溶能项外，还包括导致结合亲和力增强的蛋白质-配体结构基元：(1)疏水封闭，其中亲脂配体原子被亲脂的蛋白质原子包围在相对的面上，(2)疏水封闭环境中的中性-中性单一或相关氢键，以及(3)五类带电氢键。已经开发了XP评分功能和对接方案，以再现一组198个络合物的实验结合亲和力(所有和良好对接的配体的RMSD分别为2.26和1.73千卡/摩尔)，并为一组具有药学重要性的15个筛选产生质量浓缩。富集结果表明，新的XP分子识别和水分数在分离活性和非活性配体和避免假阳性方面具有重要意义。
A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (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 protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.