Bordas B, Belai I, Lopata A, Szanto Z
Plant Protection Institute, Hungarian Academy of Sciences, P.O. Box 102, H-1525 Budapest, Hungary.
J Chem Inf Model. 2007 Jan-Feb;47(1):176-85. doi: 10.1021/ci600317v.
A method is presented for the interpretation of receptor docking score values (rough measures of binding affinities) of ligands in terms of 3D molecular field interaction contributions. The FlexX and FlexX-Pharm methods were used to dock the structures of designed sets of ligands into the ligand-binding pocket of a selected receptor. In the next step the relationship was investigated between the FlexX and CScore scores and 3D molecular fields obtained for the docked conformations of the ligands, using the CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) methods. The approach yielded highly significant CoMFA and CoMSIA models demonstrating that a high portion of the variance in the docking score values of the ligands can be explained by steric, electrostatic, hydrophobic, and hydrogen bond donor and acceptor molecular field interaction contributions. The approach was exemplified by using the crystal structure of the ligand-binding domain of the ecdysone receptor (EcR) of the moth Heliotis virescens as well as virtual molecule libraries of analogues of known diacyl-hydrazine (DAH) type ecdysteroid agonists. By docking appropriately designed virtual compound libraries into the DAH binding pocket of EcR followed by CoMFA and CoMSIA of the docked conformations, hitherto unexplored regions of the receptor cavity could be mapped. By mapping the significant molecular field interaction contributions onto the model of the receptor-ligand complex, important receptor-ligand interactions could be highlighted that may help the design of novel highly scored receptor ligands. An advantage of the method is that no experimental biological activity data are required to exhaustively map the receptor-binding site.
本文提出了一种根据3D分子场相互作用贡献来解释配体受体对接得分值（结合亲和力的粗略度量）的方法。使用FlexX和FlexX-Pharm方法将设计的配体集结构对接至选定受体的配体结合口袋中。下一步，使用比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）方法，研究FlexX和CScore得分与配体对接构象所获得的3D分子场之间的关系。该方法产生了高度显著的CoMFA和CoMSIA模型，表明配体对接得分值的很大一部分方差可以由空间、静电、疏水以及氢键供体和受体分子场相互作用贡献来解释。以棉铃虫蜕皮激素受体（EcR）配体结合域的晶体结构以及已知二酰肼（DAH）型蜕皮甾类激动剂类似物的虚拟分子库为例来说明该方法。通过将适当设计的虚拟化合物库对接至EcR的DAH结合口袋，然后对对接构象进行CoMFA和CoMSIA，可以绘制出受体腔迄今未探索的区域。通过将显著的分子场相互作用贡献映射到受体-配体复合物模型上，可以突出重要的受体-配体相互作用，这可能有助于设计新型高分受体配体。该方法的一个优点是，无需实验生物活性数据即可详尽地绘制受体结合位点。
