Unveiling clinically significant PPARγ mutations for thiazolidinedione treatment responsiveness through atomistic simulations.

Autor: Shahrear S; Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh., Islam ABMMK; Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh. Electronic address: khademul@du.ac.bd.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2023 Dec 31; Vol. 253 (Pt 4), pp. 126990. Date of Electronic Publication: 2023 Sep 21.
DOI: 10.1016/j.ijbiomac.2023.126990
Abstrakt: In Type 2 diabetes, increased insulin sensitivity is induced by thiazolidinedione activation of the peroxisome proliferator-activated receptor gamma (PPARγ). Recent data indicate a relationship between SNPs in PPARγ and poor drug response. Therefore, understanding the pathogenic consequences of mutations in PPARγ-mediated protein-drug interactions will be prima-facie for establishing personalized medicine. The PPARG gene has 197 missense SNPs, 22 of which were determined to be both deleterious and destabilizing, employing in silico approaches. Molecular docking analysis suggested that the mutation influenced the binding energy of at least seven of the variants. The mutant R316H was identified as the most damaging and deleterious from the observed results. For a better understanding of the dynamic variation upon mutation at the atomic level, molecular dynamics simulations of the wild-type and R316H mutant PPARγ structure were performed. The analysis indicates that the mutation increased protein structural compactness while decreasing flexibility. The reduced dynamics in the mutant structure was further validated by principal component analysis. This mechanistic evaluation of the PPARγ protein variants provides insight into the relationship between genetic variation and interindividual variability of drug responsiveness and will facilitate the future studies for the development of tailored treatment regime for precision medicine.
Competing Interests: Declaration of competing interest All authors declared that they have no conflict of interest.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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