title: Biological evaluation and structural insights for design of subtype-selective peroxisome proliferator activated receptor-α (PPAR-α) agonists.
abstract: Peroxisome proliferator activated receptors-α (PPAR-α) control the expression of several genes involved in diseases like diabetes, hyperlipidaemia, and inflammatory disorders. Herein, we report the biological evaluation of recently identified hits from pharmacophore based virtual screening. The most potent hits, ZINC17167211, ZINC06472206 and ZINC08438472 showed EC50 values of 0.16, 1.1 and 12.1nM in PPAR-α agonist assay, respectively. Further, comparative docking and molecular dynamics analysis of selective PPAR-α agonists revealed that Thr279, Ala333, Lys358 and Met325 residues play an important role in the selective PPAR-α agonistic activity. The insights from docking and molecular dynamic studies will serve as a guideline for the development of potent and selective PPAR-α agonists.
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Rahul P
authors.initials: RP
authors.lastname: Gangwal
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Mangesh V
authors.initials: MV
authors.lastname: Damre
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Das
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar, Punjab 160 062, India. Electronic address: abhays@niper.ac.in.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
mesh_terms: D000083:Acetanilides / Q000737:chemistry* / Q000494:pharmacology*; D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D010795:Phthalic Acids / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*; D062366:para-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000083:Acetanilides; D000814:Aniline Compounds; D047493:PPAR alpha; D010795:Phthalic Acids; D045162:Thiazolidinediones; D013876:Thiophenes; C000601360:ZINC06472206; C000601361:ZINC08438472; C000601359:ZINC17167211; D062366:para-Aminobenzoates
keywords: Molecular docking; PPAR-α; Pharmacophore; Virtual screening