Understanding PPAR-δ affinity and selectivity using hologram quantitative structure-activity modeling, molecular docking and GRID calculations

Aim: Type 2 diabetes mellitus and metabolic syndrome are two diseases related to disorders of lipid and carbohydrate metabolism and insulin resistance. Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that control the metabolism of lipids/carbohydrates and are considered targets for both diseases. PPAR affinity and selectivity are critical points to design drug candidates with appropriated pharmacodynamic/kinetic profiles.

Materials & methods: Hologram quantitative structure-activity relationships studies were conducted, as well molecular docking and molecular interaction field calculations, in order to explain affinity and selectivity of selected compounds.

Results: The constructed hologram quantitative structure-activity relationship models are robust and predictive (values of q² and r²_test above 0.70).

Conclusion: The quantitative structure-activity relationship models and docking/GRID analyses indicated that carboxyl group of indole-sulfonamide derivatives could interact at helix-3 region, being considered important point of PPAR-δ selectivity.