Structural Requirement of PPARα Agonist Through QSARs and Molecular Simulation Analyses

Structural Requirement of PPARα Agonist Through QSARs and Molecular Simulation Analyses

Ashis Nandy, Achintya Saha
Copyright: © 2017 |Pages: 16
DOI: 10.4018/IJQSPR.2017010105
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Abstract

The present approach has aimed to investigate the physicochemical and structural requirements of a molecule to impart potential and selective PPARa agonistic activity using various ligand-based and structure-based molecular modeling techniques. These studies suggest the presence oxo heterocyclic ring connected with lipophilic substituents (phenyl, flurophenyl or any hydropbic alkyl chain) may responsible for hydrophobic interaction with the receptor. Both regression-based and classification-based QSAR, and HQSAR models infer that the ether linkage is very crucial for the activity, where as long alkyl chain or acyclic ring and the chloride substituent have detrimental effects. The pharmacophore models strongly depict the presence of two acceptors and hydrophobic region are very much essential for promising activity. The docking and MD studies suggest the presence of carboxyl group is essential for H-bond interaction with catalytic residues. The cheminformatics study provides key information on the structural pattern for imparting of potent and selective PPARa modulators.
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2. Materials And Methods

2.1. Dataset

A pool of 104 PPARα agonists (Dhoke et al., 2012) with considerable structure and activity variations was selected for the present study (supplementary file, Table 1). The effective concentration (EC50 in μM) in terms of pEC50 (log106/EC50) was used as the dependent variable, except hyporefine-based pharmacophore mapping where EC50 was used for molecular modeling analyses. The dataset was divided into training (Tr) and test (Ts) sets for model development and validation purposes, respectively.

Data Sets

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