Exploring Dual Agonists for PPARα/γ Receptors using Pharmacophore Modeling, Docking Analysis and Molecule Dynamics...

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Molecular Pharmacology

Background:

• Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptors regulating metabolism.
• PPARα is key in fatty acid oxidation, while PPARγ influences adipocyte differentiation and lipid storage.
• Dual PPARα/γ agonists offer a therapeutic strategy for hyperglycemia, hyperlipidemia, and cardiovascular complications.

Purpose of the Study:

• To design and identify novel dual PPARα/γ agonists with potential therapeutic benefits.
• To combine insulin sensitization and lipid-lowering effects into a single drug candidate.
• To develop compounds for managing metabolic disorders and preventing cardiovascular issues.

Main Methods:

• Pharmacophore modeling and virtual screening of a large molecular database (Ligand Expo Components-pub).
• Structural modification of identified ligands to create novel compounds.
• Molecular docking, ADMET prediction, and molecular dynamics simulations for screening and verification.

Main Results:

• Pharmacophore-based virtual screening identified lead compounds from 22,949 molecules.
• Structural modifications yielded 12 new potential dual PPARα/γ agonists.
• Computational analyses confirmed higher docking scores and predicted lower side effects for the designed compounds.

Conclusions:

• Nine novel dual PPARα/γ agonists were successfully identified through integrated computational approaches.
• These compounds represent promising candidates for further development in treating metabolic diseases.
• The study highlights the efficacy of virtual screening and molecular dynamics in drug discovery.