作为5-HT6拮抗剂的N1-芳基磺酰基吲哚化合物的比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）三维定量构效关系研究

CoMFA and CoMSIA 3D QSAR analysis on N1-arylsulfonylindole compounds as 5-HT6 antagonists.

作者信息

Doddareddy Munikumar Reddy, Cho Yong Seo, Koh Hun Yeong, Pae Ae Nim

机构信息

Biochemicals Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, South Korea.

出版信息

Bioorg Med Chem. 2004 Aug 1;12(15):3977-85. doi: 10.1016/j.bmc.2004.06.007.

DOI:10.1016/j.bmc.2004.06.007

PMID:15246074

Abstract

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series of N(1)-arylsulfonylindole compounds as 5-HT(6) antagonists. Evaluation of 20 compounds served to establish the models. The lowest energy conformer of compound 1 obtained from random search was used as template for alignment. The best predictions were obtained with CoMFA standard model (q2 = 0.643, r2 = 0.939 ) and with CoMSIA combined steric, electrostatic, hydrophobic, and hydrogen bond acceptor fields (q2 = 0.584, r2 = 0.902 ). Both the models were validated by an external test set of eight compounds giving satisfactory predictive r2 values of 0.604 and 0.654, respectively. The information obtained from CoMFA and CoMSIA 3D contour maps can be used for further design of specific 5-HT(6) antagonists.

摘要

对一系列作为5-羟色胺（5-HT）6拮抗剂的N(1)-芳基磺酰基吲哚化合物进行了比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）三维定量构效关系（3D-QSAR）研究。对20种化合物的评估用于建立模型。从随机搜索获得的化合物1的最低能量构象用作比对模板。使用CoMFA标准模型（交叉验证系数q2 = 0.643，决定系数r2 = 0.939）以及CoMSIA结合空间、静电、疏水和氢键受体场（q2 = 0.584，r2 = 0.902）时得到了最佳预测结果。两个模型均通过由8种化合物组成的外部测试集进行验证，预测r2值分别为0.604和0.654，结果令人满意。从CoMFA和CoMSIA 3D等高线图获得的信息可用于进一步设计特定的5-HT6拮抗剂。