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

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.

Discovery of Anti-Hypertensive Oligopeptides from Adlay Based on In Silico Proteolysis and Virtual Screening

“…–CDOCKER ENERGY (kcal/mol) was the scoring function of CDOCKER algorithm, which represented the energy of the ligand–receptor complexes [35]. Fifty percent of –CDOCKER ENERGY for three crystal structures were regarded as the threshold for screening the potential ACE inhibitory oligopeptides [36,37]. …”

Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine

“…Null Cost of ten hypotheses was 228.61, and △cost was difference value between Null Cost minus Total Cost of each hypothesis. The △cost value of ten hypotheses greater than 60 indicated that there is generally a high probability and low contingency of models 31 . From the Table 1, correlation values between predicted and experimental activity of training set for pharmacophore models were greater than 0.8, which indicated pharmacophore models had better ability to predict activity of compounds 31 .…”

“…The △cost value of ten hypotheses greater than 60 indicated that there is generally a high probability and low contingency of models 31 . From the Table 1, correlation values between predicted and experimental activity of training set for pharmacophore models were greater than 0.8, which indicated pharmacophore models had better ability to predict activity of compounds 31 . Then testing set was used to compute external indexes of the pharmacophore models in order to analyze the capabilities of identifying active compounds from non-active compounds and distinguishing the higher activity compounds from lower activity compounds.…”

Discovery of pharmacological effects and targets of Citri Grandis Exocarpium based on SYSTCM and virtual screening

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