Biological evaluation and structural insights for design of subtype-selective peroxisome proliferator activated receptor-α (PPAR-α) agonists. Issue 2 (15th January 2015)

• Record Type: Journal Article
• Authors: Gangwal, Rahul P.; Damre, Mangesh V.; Das, Nihar R.; Sharma, Shyam S.; Sangamwar, Abhay T.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 2(2015)
• Page Start: 270
• Page End: 275
• Publication Date: 2015-01-15
• Subjects: Molecular docking -- PPAR-α -- Pharmacophore -- Virtual screening; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2014.11.052
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 12.1 nM 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.