To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations

Abstract

Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPARγ and a partial activation of PPARα and PPARβ/δ). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPARα, PPARβ/δ, and PPARγ, followed by 3 μs molecular dynamics simulations for each system. Our MM-GBSA binding energy calculation revealed that chiglitazar most favorably bound to hPPARγ (-144.6 kcal/mol), followed by hPPARα (-138.0 kcal/mol) and hPPARβ (-135.9 kcal/mol), and the order is consistent with the experimental data. Through the decomposition of the MM-GBSA binding energy by residue and the use of two-dimensional interaction diagrams, key residues involved in the binding of chiglitazar were identified and characterized for each complex system. Additionally, our detailed dynamics analyses support that the conformation and dynamics of helix 12 play a critical role in determining the activities of the different types of ligands (e.g., full agonist vs. partial agonist). Rather than being bent fully in the direction of the agonist versus antagonist conformation, a partial agonist can adopt a more linear conformation and have a lower degree of flexibility. Our finding may aid in further development of this new generation of medication.

Novel Thiazolidinedione and Rhodanine Derivatives Regulate Glucose Metabolism, Improve Insulin Sensitivity, and Activate the Peroxisome Proliferator-Activated γ Receptor

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Phytochemical Characterization and Anticancer Screening of Cladophora goensis and Cladophora glomerata Extracts

“…27 Phytol interaction at LEU'321 was shown to be a significant agonistic activity site for PPAR alpha protein to exhibit anticancer as well as antidiabetic activity. 28 Also, in vitro studies in the HT-29 cancer cell line, with the extracts of C. goensis show significant anti-cancer activity. 29 The presence of hexadecanoic acid in C. glomerata was also reported by other studies.…”

Chiglitazar and Thiazolidinedione in patients with type 2 diabetes: Which is better?

“…With a diabetes pandemic in visibility, there is an urgent need of newer molecules and modality of treatments for type 2 diabetes mellitus, Chiglitazar represents a new wave of non- thiazolidinedione medications that can regulate gene expression by binding in a configuration-restricted manner and inhibiting the phosphorylation of hPPARγ, Chiglitazar operates as a pan-agonist, offering a detailed mechanism that elucidates its ability to fully activate PPARγ and partially activate PPARα and PPARβ[ 2 ].…”