Pharmacophore-based similarity scoring for DOCK.
Pharmacophore-based similarity scoring for DOCK.
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DOI：
10.1021/jp506555w
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发表时间：
2015-01-22
期刊：
影响因子：
--
通讯作者：
Rizzo RC
中科院分区：
文献类型：
--
作者：
Jiang L;Rizzo RC
药效团建模结合了已知抑制剂和/或靶向结合位点的几何和化学特征，以合理地识别和设计新药先导物。在这项研究中，我们已经编码的三维药效团匹配相似性（FMS）评分功能到基于结构的设计程序DOCK。该方法的验证和表征，提出通过姿势再现，crossdocking，和富集研究。当单独使用时，FMS评分显着提高姿势再现成功率至93.5%（增加20%），并将采样失败率降低至3.7%（下降6%），与标准能量评分（SGE）相比，1043个蛋白质-配体复合物。FMS+SGE组合功能进一步将成功率提高至98.3%。使用FMS和FMS+SGE评分的六个不同蛋白质家族的交叉对接实验同样显示出成功的改善，前提是采用适当的药效团参考。对于富集，在采样和评分过程中掺入药效团，在大多数情况下，当将已知活性物质和诱饵的文库对接和排序到15个系统时，也会产生改进的结果。还报告了使用已知抑制剂的X射线结构作为药效团参考对三种临床药物靶点（EGFR，IGF-1 R和HIVgp 41）进行虚拟筛选的回顾性分析，包括定制的FMS评分方案，以在参考中的选定区域上进行偏倚。总的来说，从这项研究中获得的结果和基本见解应该有利于对接社区，特别是使用新的FMS方法来指导DOCK计算药物发现的研究人员。
Pharmacophore modeling incorporates geometric and chemical features of known inhibitors and/or targeted binding sites to rationally identify and design new drug leads. In this study, we have encoded a three-dimensional pharmacophore matching similarity (FMS) scoring function into the structure-based design program DOCK. Validation and characterization of the method are presented through pose reproduction, crossdocking, and enrichment studies. When used alone, FMS scoring dramatically improves pose reproduction success to 93.5% (∼20% increase) and reduces sampling failures to 3.7% (∼6% drop) compared to the standard energy score (SGE) across 1043 protein–ligand complexes. The combined FMS+SGE function further improves success to 98.3%. Crossdocking experiments using FMS and FMS+SGE scoring, for six diverse protein families, similarly showed improvements in success, provided proper pharmacophore references are employed. For enrichment, incorporating pharmacophores during sampling and scoring, in most cases, also yield improved outcomes when docking and rank-ordering libraries of known actives and decoys to 15 systems. Retrospective analyses of virtual screenings to three clinical drug targets (EGFR, IGF-1R, and HIVgp41) using X-ray structures of known inhibitors as pharmacophore references are also reported, including a customized FMS scoring protocol to bias on selected regions in the reference. Overall, the results and fundamental insights gained from this study should benefit the docking community in general, particularly researchers using the new FMS method to guide computational drug discovery with DOCK.
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影响因子：
2.9
作者：
Huang, Yulin;Rizzo, Robert C.
通讯作者：
Rizzo, Robert C.
影响因子：
--
作者：
Ehrlich, P
通讯作者：
Ehrlich, P
影响因子：
5.6
作者：
Allen WJ;Rizzo RC
通讯作者：
Rizzo RC
DOI：
10.1021/ci034207y
发表时间：
2004-01-01
期刊：
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
影响因子：
--
作者：
Bender, A;Mussa, HY;Reiling, S
通讯作者：
Reiling, S
DOI：
10.1021/ci950273r
发表时间：
1996-05-01
期刊：
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
影响因子：
--
作者：
Barnum, D;Greene, J;Sprague, P
通讯作者：
Sprague, P