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


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 q2and r2testabove 0.70).


CONCLUSIONS
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.
Pharmaceutical Products Department, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte - MG, Brazil.
Vinicius G
VG
Maltarollo
Center of Natural & Humanity Sciences, Federal University of ABC, Santo André, SP, Brazil.
Sheila C
SC
Araujo
Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Gustavo H
GH
G Trossini
Center of Natural & Humanity Sciences, Federal University of ABC, Santo André, SP, Brazil.|School of Arts, Sciences & Humanities, University of São Paulo, São Paulo, SP, Brazil.
Kathia M
KM
Honorio
GRID; HQSAR; PPAR; diabetes mellitus; docking; metabolic syndrome; selectivity