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Construction and Evaluation of Merged Pharmacophore Based on Peroxisome Proliferator Receptor-Alpha Agonists
Authors:Lian-sheng Qiao  Yu-su He  Xiao-qian Huo  Lu-di Jiang  Yan-kun Chen  Xi Chen  Yan-ling Zhang  Gong-yu Li
Institution:Beijing Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China
Abstract: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 distinguishing 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 peroxisome 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.
Keywords:Merged pharmacophore  Ligand-based pharmacophore  Structure-based pharmacophore  Peroxisome proliferator receptor-alpha  Docking  Combinatorial screening
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