IDENTIFICATION OF NOVEL PPARγ MODULATORS / PARTIAL AGONISTS THROUGH VIRTUAL SCREENING WORKFLOW

Thiazolidinedione’s (TZDs) being insulin sensitizer’s act as agonists of PPARγ used in the treatment of type 2 diabetes but suffered with serious side effects. After understanding the trans-activation mechanism of PPAR receptors and in order to overcome these side effects a new path has been led to new approaches like, PPAR-α/γ dual agonists, PPAR-δ/γ dual agonists, PPAR-pan agonists, selective PPAR-γ modulators (SPPARγMs) / partial agonists. Among them SPPARγMs) / partial agonists attracted due to their selectivity and expression in the selective tissue. The present study aims at identifying novel SPPARγMs) / partial agonists by using VS workflow and molecular docking. Virtual screening workflow is fallowed which consists of several steps like (a) Ligand based anti-pharmacophore screening(b) Ligand based Pharmacophore screening (c) ADME /Toxicity analysis and (d) Molecular Docking. Out of 21,818 molecules subjected to anti pharmacophore model, 4936 molecules qualify for the next step i.e., pharmacophore model screening. Out of these molecules only 12 molecules showed Qfit > 70. Therefore, these molecules were further subjected to ADME /TOX filter step in which 7 molecules passed the step. Further these molecules subjected to docking studies. In the docking studies based on the typical binding modes of the standard partial agonist (INT131) 5 molecules were found to have good binding mode required for a typical partial agonist. The Virtual screening workflow used in the study identifies 5 molecules as partial agonists.

• Publication year

  2019

• Venue

  International Research Journal of Pharmacy

• Publication date

  2019-12-06

• Fields of study

  Medicine, Chemistry, Computer Science

• Identifiers
  DOI 10.7897/2230-8407.1011321
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Diabetes and Metabolic Syndrome: Clinical Research and Reviews

  2018cited by this paper
• Thiazolidinediones and Edema: Recent Advances in the Pathogenesis of Thiazolidinediones-Induced Renal Sodium Retention

  2015cited by this paper
• Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation

  2012cited by this paper
• Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism.

  2012cited by this paper
• The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases

  2011cited by this paper
• A Combined Ligand‐ and Structure‐Based Virtual Screening Protocol Identifies Submicromolar PPARγ Partial Agonists

  2011cited by this paper
• Pioglitazone: Indian perspective

  2011cited by this paper
• Revisiting the rosiglitazone story--lessons learned.

  2010cited by this paper
• Fibrates, Glitazones, and Peroxisome Proliferator–Activated Receptors

  2010cited by this paper
• Pioglitazone: side effect and safety profile

  2010cited by this paper
• INT131: A Selective Modulator of PPARγ

  2009cited by this paper
• Development of Synthetic Modulators of PPARs: Current Challenges and Future Opportunities

  2009cited by this paper
• The Differential Interactions of Peroxisome Proliferator-Activated Receptor γ Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities

  2008cited by this paper
• Glitazones: Beyond glucose lowering!

  2007cited by this paper
• Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators.

  2007cited by this paper
• Partial agonists activate PPARgamma using a helix 12 independent mechanism.

  2007cited by this paper
• A Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor- (cid:1) (PPAR (cid:1) ) Recruits PPAR (cid:1) -Coactivator-1 (cid:2) , Prevents Triglyceride Accumulation, and Potentiates Insulin Signaling in Vitro

  2006cited by this paper
• Troglitazone: the lesson that nobody learned?

  2005cited by this paper
• Coregulator function: a key to understanding tissue specificity of selective receptor modulators.

  2004cited by this paper
• Rosiglitazone and pulmonary oedema: an acute dose-dependent effect on human endothelial cell permeability

  2003cited by this paper
• Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation

  2003cited by this paper
• Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription.

  2000cited by this paper
• A peroxisome proliferator-activated receptor g ligand inhibits adipocyte differentiation

  1999cited by this paper
• PPARγ Mediates High-Fat Diet–Induced Adipocyte Hypertrophy and Insulin Resistance

  1999cited by this paper
• Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ

  1998cited by this paper
• Hepatic dysfunction associated with troglitazone.

  1998cited by this paper
• An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ) (*)

  1995cited by this paper

• No citing papers are available for this paper.