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 low...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.展开更多
文摘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.
