5-HT_6受体拮抗剂三维定量构效关系研究

Study of 3D-QSAR of 5-HT_6 receptor antagonists

为指导合成高效的5-HT6受体拮抗剂,采用比较分子场分析(CoMFA)和比较相似性指数分析(CoMSIA)对143个5-HT6受体拮抗剂数据进行了三维定量构效关系(3D-QSAR)研究,分别得到了具有良好可靠性和预测能力的CoMFA(Q2=0.513,R2ncv=0.864,R2pre=0.731)和CoMSIA模型(Q2=0.515,R2ncv=0.844,R2pre=0.777).由模型的等势线图分析,可得如下结论:大体积及/或电负性较大的R2取代基、疏水性R3和疏水性苯环R1位取代基、可作氢键受体的R2取代基、可作氢键供体的R3取代基有助于增大活性.这些结论能够更好地帮助理解5-HT6受体拮抗剂的抑制机理,并为今后的药物设计与合成提供新思路.

Based on a data set of 143 5-HT6 antagonists,comparative molecular field analysis（CoMFA） and comparative molecular similarity indices analysis（CoMSIA） were carried out to aid in the design of 5-HT6 antagonists with potent activity to build 3-dimensional quantitative structure-activity relationship（3D-QSAR） models.The results show that both the optimal CoMFA（Q2=0.513,R2ncv=0.864,R2pre=0.731） and CoMSIA（Q2=0.515,R2ncv=0.844,R2pre=0.777） models have good reliabilities and predictive abilities.Additionally,from the analysis of the contour maps,it can be concluded that bulky R2 substituent with/or without negatively charges,hydrophobic groups both in R3 and R1 substituent at the benzene ring,HB acceptor substituent in R2 and HB donor substituent in R3 will benefit the activity.All the conclusions can supply useful information for better understanding of the mechanism of 5-HT6 antagonism and are also helpful in providing new clues for drug design and synthesis.