Biological evaluation and structural insights for design of subtype-selective peroxisome proliferator activated receptor-α (PPAR-α) agonists

Bioorg Med Chem Lett. 2015 Jan 15;25(2):270-5. doi: 10.1016/j.bmcl.2014.11.052. Epub 2014 Nov 26.

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.

Keywords: Molecular docking; PPAR-α; Pharmacophore; Virtual screening.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / chemistry*
  • Acetanilides / pharmacology*
  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacology*
  • Combinatorial Chemistry Techniques
  • Drug Design*
  • Drug Evaluation, Preclinical / methods*
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • PPAR alpha / agonists*
  • Phthalic Acids / chemistry*
  • Phthalic Acids / pharmacology*
  • Structure-Activity Relationship
  • Thiazolidinediones / chemistry*
  • Thiazolidinediones / pharmacology*
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology*
  • para-Aminobenzoates / chemistry*
  • para-Aminobenzoates / pharmacology*

Substances

  • Acetanilides
  • Aniline Compounds
  • PPAR alpha
  • Phthalic Acids
  • Thiazolidinediones
  • Thiophenes
  • ZINC06472206
  • ZINC08438472
  • ZINC17167211
  • para-Aminobenzoates