Understanding PPAR-δ affinity and selectivity using hologram quantitative structure-activity modeling, molecular...

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Type 2 diabetes mellitus and metabolic syndrome involve lipid/carbohydrate metabolism and insulin resistance.
• Peroxisome proliferator-activated receptors (PPARs) regulate these metabolic processes and are key drug targets.
• Optimizing PPAR affinity and selectivity is crucial for effective drug development.

Purpose of the Study:

• To elucidate the structural determinants of affinity and selectivity for PPAR modulators.
• To develop predictive models for designing novel drug candidates targeting PPARs.

Main Methods:

• Hologram quantitative structure-activity relationship (HQSAR) studies were employed.
• Molecular docking and molecular interaction field (MIF) calculations were performed.
• Structure-activity relationships were analyzed to explain compound interactions.

Main Results:

• Robust and predictive HQSAR models were constructed, with q² and r²test values exceeding 0.70.
• Analysis identified the carboxyl group of indole-sulfonamide derivatives as critical for PPAR interaction.
• Specific interactions were pinpointed within the helix-3 region of the PPAR receptor.

Conclusions:

• The carboxyl group of indole-sulfonamide derivatives is a key pharmacophore for PPAR-δ selectivity.
• These findings provide a rational basis for designing selective PPAR modulators.
• The study highlights the utility of integrated computational approaches in drug discovery.