Guo Yanshen, Xiao Jingfa, Guo Zongru, Chu Fengming, Cheng Yonghao, Wu Song
Department of Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Bioorg Med Chem. 2005 Sep 15;13(18):5424-34. doi: 10.1016/j.bmc.2005.05.016.
Docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses were conducted on a series of indole amide analogues as potent histone deacetylase inhibitors. The studies include comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Selected ligands were docked into the active site of human HDAC1. Based on the docking results, a novel binding mode of indole amide analogues in the human HDAC1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. The indole amide group is located in the open pocket, and anchored to the protein through a pair of hydrogen bonds with Asp99 O-atom and amide NH group on ligand. Based on the binding mode, predictive 3D-QSAR models were established, which had conventional r2 and cross-validated coefficient values (r(cv)2) up to 0.982 and 0.601 for CoMFA and 0.954 and 0.598 for CoMSIA, respectively. A comparison of the 3D-QSAR field contributions with the structural features of the binding site showed good correlation between the two analyses. The results of 3D-QSAR and docking studies validate each other and provided insight into the structural requirements for activity of this class of molecules as HDAC inhibitors. The CoMFA and CoMSIA PLS contour maps and MOLCAD-generated active site electrostatic, lipophilicity, and hydrogen-bonding potential surface maps, as well as the docking studies, provided good insights into inhibitor-HDAC interactions at the molecular level. Based on these results, novel molecules with improved activity can be designed.
对一系列作为有效组蛋白脱乙酰酶抑制剂的吲哚酰胺类似物进行了对接模拟和三维定量构效关系(3D-QSAR)分析。这些研究包括比较分子场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)。将选定的配体对接至人HDAC1的活性位点。基于对接结果,提出了吲哚酰胺类似物在人HDAC1催化核心中的一种新型结合模式,并讨论了酶/抑制剂相互作用。吲哚酰胺基团位于开放口袋中,并通过与配体上Asp99的O原子和酰胺NH基团形成的一对氢键锚定在蛋白质上。基于这种结合模式,建立了预测性3D-QSAR模型,对于CoMFA,其传统的r2和交叉验证系数值(r(cv)2)分别高达0.982和0.601,对于CoMSIA则分别为0.954和0.598。3D-QSAR场贡献与结合位点结构特征的比较表明,这两种分析之间具有良好的相关性。3D-QSAR和对接研究的结果相互验证,并为这类分子作为HDAC抑制剂的活性结构要求提供了深入了解。CoMFA和CoMSIA的PLS等高线图以及MOLCAD生成的活性位点静电、亲脂性和氢键势表面图,以及对接研究,在分子水平上为抑制剂与HDAC的相互作用提供了很好的见解。基于这些结果,可以设计出活性得到改善的新型分子。