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.
Highlights
In the year 1999, the World Health Organization estimated that by 2025 roughly 300 million people would be suffering from diabetes
For the peroxisome proliferator-activated receptors (PPARs), several structural features are conserved amongst the receptor subtypes (PPARα, PPARβ, and PPARγ) which include the activation function 1 (AF-1), DNA binding domain (DBD), activation function 2 (AF-2), and ligandbinding domain (LBD) [58, 103, 104] whose sequence alignment is presented in Figure 1 and shows a 65% homology amongst the three subtypes [15, 27, 104]
With type 2 diabetes mellitus (T2DM) affecting such a broad range of the population, there is a dire need for effective treatment with minimal side effects
Summary
In the year 1999, the World Health Organization estimated that by 2025 roughly 300 million people would be suffering from diabetes. In 2014, the World Health Organization reported 422 million people suffering from diabetes worldwide, surpassing the estimate by a shocking 122 million people with 11 years to spare. This statistic highlights the ongoing and crucial need for an effective treatment for type II diabetes mellitus (T2DM) [1,2,3]. Human peroxisome proliferator-activated receptors (PPARs) belong to a subfamily of nuclear hormone receptors that act as ligand-activated transcription factors to regulate a variety of biological processes including glucose metabolism, lipoprotein metabolism, and immune response [4,5,6].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
