Molecular Modeling Study of PPARr Agonists: Dehydro-Di-Isoeugenol, Macelignan, Pioglitazone, Netoglitazone, and Rosiglitazone as Antidiabetic Drugs

Nyi Mekar Saptarini, Febrina Amelia Saputri, Jutti Levita


The peroxisome proliferator-activated receptors (PPARs) are ligand-activated trasncription factors belonging to the nuclear receptor family. The objective of this study is to analyze the molecular aspects of PPARr agonists which used to design of new antidiabetic drugs. The analysis method was comparing the interactions of ligands in the ligand binding domain of the PPARr. This analysis showed that most known agonists of PPARr interacted via hydrogen bond with Tyr473. Pioglitazone showed three hydrogen bonds with His323 and Tyr473. Netoglitazone showed four hydrogen bonds with Ser289, His323, His449, and Tyr473. Rosiglitazone showed five hydrogen bonds with Ser289, His323, His449, and Tyr473. AZ72, an agonist of PPARr and r showed five hydrogen bonds with Ser289, His323, His449, and Tyr473. Molecular modeling was performed by redocking pioglitazone and rosiglitazone using AutoDock Vina. Docking showed that both pioglitazone (Ki 0.22 uM) and rosiglitazone (Ki 0.70 uM) occupied their origin sites and interacted with Tyr473. Docking simulation was also performed between dehydro-di-isoeugenol and macelignan to visualize the interaction with PPARr. These two compounds are found in nutmeg’s seed (Myristica fragrans Hout) that have been proven had antidiabetic activity in vitro. It can be concluded that agonists of PPARr should have hydrogen bond donor and acceptor groups for interacting with Tyr473. Tyr473 might be a critical site of interaction between the PPARr ligand binding domain and its agonists.

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International Journal of Chemistry   ISSN 1916-9698 (Print)   ISSN 1916-9701 (Online)

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