Ligand Mapping on Protein Surfaces by the 3D-RISM Theory: Toward Computational Fragment-Based Drug Design
Ligand Mapping on Protein Surfaces by the 3D-RISM Theory: Toward Computational Fragment-Based Drug Design
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DOI：
10.1021/ja905029t
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发表时间：
2009-09-02
影响因子：
15
通讯作者：
Kidera, Akinori
中科院分区：
文献类型：
--
作者：
Imai, Takashi;Oda, Koji;Kidera, Akinori
根据基于片段的药物设计的最新发展，提出了一种新的蛋白质表面小配体分子定位的计算方法。该方法利用分子溶剂化理论（即3D参考相互作用位点模型（3D- rism）理论）计算出配体原子位点的三维空间分布函数，以确定配体分子最可能的结合模式。将基于3d - rism的方法应用于几种有机小分子与热溶酶的结合，以显示其检测结合位点的效率和准确性。结果表明，我们的方法能够以足够的精度再现x射线晶体学研究中发现的主要结合模式。此外，该方法可以成功识别与已知抑制剂相关的一些结合模式，这些模式无法通过x射线分析检测到。本文还研究了配体结合模式对配体浓度的依赖性，这是其他现有计算方法无法处理的。结果表明，一些结合模式容易受到配体浓度的影响，而另一些则不明显改变。在前一种情况下，正是配体与水之间结合亲和力的微妙平衡决定了配体结合的主导模式。
In line with the recent development of fragment-based drug design, a new computational method for mapping of small ligand molecules on protein surfaces is proposed. The method uses three-dimensional (3D) spatial distribution functions of the atomic sites of the ligand calculated using the molecular theory of solvation, known as the 3D reference interaction site model (3D-RISM) theory, to identify the most probable binding modes of ligand molecules. The 3D-RISM-based method is applied to the binding of several small organic molecules to thermolysin, in order to show its efficiency and accuracy in detecting binding sites. The results demonstrate that our method can reproduce the major binding modes found by X-ray crystallographic studies with sufficient precision. Moreover, the method can successfully identify some binding modes associated with a known inhibitor, which could not be detected by X-ray analysis. The dependence of ligand-binding modes on the ligand concentration, which essentially cannot be treated with other existing computational methods, is also investigated. The results indicate that some binding modes are readily affected by the ligand concentration, whereas others are not significantly altered. In the former case, it is the subtle balance in the binding affinity between the ligand and water that determines the dominant ligand-binding mode.