Synthesis, biological evaluation, and molecular modeling investigation of chiral 2-(4-chloro-phenoxy)-3-phenyl-propanoic acid derivatives with PPARalpha and PPARgamma agonist activity.
PPARs are ligand-activated transcription factors that govern lipid and glucose homeostasis and play a central role in cardiovascular disease, obesity, and diabetes. Herein, we present screening results for a series of chiral 2-(4-chloro-phenoxy)-3-phenyl-propanoic acid derivatives, some of which are potent PPARgamma agonists as well as PPARalpha agonists. To investigate the binding modes of the most interesting derivatives into the PPARalpha and PPARgamma binding clefts and evaluate their agonist activity, docking experiments, molecular dynamics simulations, and MM-PBSA analysis were performed.
Fracchiolla
Giuseppe
G
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, via Orabona 4, 70126 Bari, Italy.
Lavecchia
Antonio
A
Laghezza
Antonio
A
Piemontese
Luca
L
Trisolini
Raffaella
R
Carbonara
Giuseppe
G
Tortorella
Paolo
P
Novellino
Ettore
E
Loiodice
Fulvio
F
D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018197:Hepatoblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; C029658:propionic acid