Deciphering the relational dynamics of AF-2 domain of PAN PPAR through drug repurposing and comparative simulations.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2023
2023
Historique:
received:
06
09
2022
accepted:
15
03
2023
medline:
4
4
2023
entrez:
31
3
2023
pubmed:
1
4
2023
Statut:
epublish
Résumé
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, and their activation has been proven to treat mild liver fibrosis, reduce steatosis, inflammation, and the extrahepatic effects of chronic liver disease. Considering the significance of the PPARs, it is targeted for the treatment of Non-Alcoholic Steatohepatitis (NASH), for which currently there is no FDA-approved drug. Lanifibranor is a next-generation highly potential indole sulfonamide derivative that is presently in clinical trial phase III as an anti-NASH drug which fully activates PPARα and PPARδ and partially activates PPARγ. In the current study, a comprehensive computational investigation including 3D-QSAR pharmacophore modeling, MD simulations and binding free energy calculations is performed to get insights into the activation mechanism of the Lanifibranor. Furthermore, FDA-approved drugs were explored for repurposing through virtual screening against each PPAR pharmacophore to identify potential drug candidates. Forasartan, Raltitrexed, and Lifitegrast stood out as potential agonists for PPARα (full agonist), PPARγ (partial agonist), and PPARδ (full agonist), respectively. The findings of the study highlighted a lack of hydrogen bond acceptor feature in Raltitrexed and Lanifibranor which is responsible for partial activation of PPARγ that plays a critical role in preventing lipid accumulation. In addition to this, the significant role of AF2 domain in full and partial activation of PPARs through electrostatic interactions was also revealed, that facilitates the anchoring of ligand within the binding cavity. Moreover, common chemical scaffolds (methyl sulfonyl benzene, butyric acid, and chlorobenzene) identified using Fingerprinting technique were presented in this study which hold the potential to aid in the design and development of target specific novel Pan PPAR medications in future.
Identifiants
pubmed: 37000796
doi: 10.1371/journal.pone.0283743
pii: PONE-D-22-24825
pmc: PMC10065303
doi:
Substances chimiques
Furylfuramide
054NR2135Y
lanifibranor
28Q8AG0PYL
PPAR alpha
0
PPAR delta
0
PPAR gamma
0
raltitrexed
FCB9EGG971
Types de publication
Clinical Trial
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0283743Informations de copyright
Copyright: © 2023 Gul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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