Gleeson M Paul, Gleeson Duangkamol
Computational & Structural Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
J Chem Inf Model. 2009 Jun;49(6):1437-48. doi: 10.1021/ci900022h.
The use of QM/MM based methods to optimize and rescore GOLD derived cross-docked protein-ligand poses has been investigated using a range of fragment-like kinase inhibitors where experimental data have been reported. Particular emphasis has been placed on rationalizing the potential benefits of the method in the increasingly popular fragment based drug discovery area. The results of this cross-docking, rescoring study on 9 protein ligand complexes suggest that the hybrid QM/MM calculations could prove useful in kinase fragment based drug discovery (FBDD). B3LYP/6-31G**//UFF derived enthalphies allow us to identify the correct X-ray pose from a range of plausible decoys 77% of the time, almost a doubling of the retrieval rate compared to GOLD (44%). In addition, this method provides us with a means to rapidly and accurately generate virtual protein-ligand complexes that will allow a program team to probe the existing interactions between the ligand and protein and search for additional interactions.
使用基于QM/MM的方法对GOLD衍生的交叉对接蛋白质-配体构象进行优化和重新评分，已在一系列已报道实验数据的类片段激酶抑制剂上展开研究。特别强调了该方法在日益流行的基于片段的药物发现领域的潜在益处。这项对9种蛋白质-配体复合物进行交叉对接、重新评分研究的结果表明，混合QM/MM计算在基于激酶片段的药物发现（FBDD）中可能会证明是有用的。B3LYP/6-31G**//UFF得出的焓使我们能够在77%的时间里从一系列合理的诱饵中识别出正确的X射线构象，与GOLD（44%）相比，检索率几乎提高了一倍。此外，该方法为我们提供了一种快速准确地生成虚拟蛋白质-配体复合物的手段，这将使项目团队能够探究配体与蛋白质之间现有的相互作用，并寻找其他相互作用。
