Construction and Evaluation of Merged Pharmacophore Based on Peroxisome Proliferator Receptor-Alpha Agonists  

基于PPARα激动剂的融合药效团模型的构建及评价

作　　者：乔连生[1] 贺昱甦 霍晓乾 蒋芦荻 陈艳昆 陈茜[1] 张燕玲[1] 李贡宇[1] 乔连生;贺昱甦;霍晓乾;蒋芦荻;陈艳昆;陈茜;张燕玲;李贡宇(北京中医药大学中药学院,中药基础与新药研究重点实验室,北京100102)

机构地区：[1]北京中医药大学中药学院,中药基础与新药研究重点实验室,北京100102

出　　处：《Chinese Journal of Chemical Physics》2016年第4期508-516,I0002,共10页化学物理学报（英文）

摘　　要：Pharmacophore is a commonly used method for molecular simulation, including ligand-based pharmacophore （LBP） and structure-based pharmacophore （SBP）. LBP can be utilized to identify active compounds usual with lower accuracy, and SBP is able to use for distin- guishing active compounds from inactive compounds with frequently higher missing rates. Merged pharmacophore （MP） is presented to integrate advantages and avoid shortcomings of LBP and SBP. In this work, LBP and SBP models were constructed for the study of per- oxisome proliferator receptor-alpha （PPARα） agonists. According to the comparison of the two types of pharmacophore models, mainly and secondarily pharmacological features were identified. The weight and tolerance values of these pharmacological features were adjusted to construct MP models by single-factor explorations and orthogonal experimental design based on SBP model. Then, the reliability and screening efficiency of the best MP model were validated by three databases. The best MP model was utilized to compute PPARα activity of compounds from traditional Chinese medicine. The screening efficiency of MP model outperformed individual LBP or SBP model for PPARα agonists, and was similar to combinatorial screening of LBP and SBP. However, MP model might have an advantage over the combination of LBP and SBP in evaluating the activity of compounds and avoiding the inconsistent prediction of LBP and SBP, which would be beneficial to guide drug design and optimization.

关 键 词：Merged pharmacophore Ligand-based pharmacophore Structure-based pharmaeophore Peroxisome proliferator receptor-alpha DOCKING Combinatorial screening 

分 类 号：O4[理学—物理]