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Unveiling structural determinants for FXR antagonism in 1,3,4-trisubstituted-Pyrazol amide derivatives: A multi-scale in silico modelling approach.
- Source :
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Computers in biology and medicine [Comput Biol Med] 2024 Sep; Vol. 180, pp. 108991. Date of Electronic Publication: 2024 Aug 09. - Publication Year :
- 2024
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Abstract
- Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern due to its potential to progress into severe liver diseases. Targeting the bile acid receptor FXR has emerged as a promising strategy for managing NAFLD. Building upon our previous research on FXR partial agonism, the present study investigates a series of 1,3,4-trisubstituted-pyrazol amide derivatives as FXR antagonists, aiming to delineate the structural features for antagonism. By means of 2D-QSAR (quantitative structure-activity relationships) modelling techniques, we elucidated the key structural elements responsible for the antagonistic properties of these derivatives. We then employed QPhAR, an open-access software, to identify key molecular features within the compounds that enhance their antagonistic activity. Additionally, 3D-QSAR modelling allowed us to analyse the steric and electrostatic fields of aligned 3D structures, further refining our understanding of structure-activity relationships. Subsequent molecular dynamics simulations provided insights into the binding mode interactions between the compounds and FXR, with varying potencies, confirming and complementing the findings from 2D-QSAR, pharmacophore, and 3D-QSAR modelling. Particularly, our study highlighted the significance of hydrophobic interactions in conferring potent antagonism by the 1,3,4-trisubstituted-pyrazol amide derivatives against FXR. Overall, this work underscores the potential of 1,3,4-trisubstituted-pyrazol amides as FXR antagonists for NAFLD treatment. Notably, our reliance on open-access software fosters reproducibility and broadens the accessibility of our findings.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Subjects :
- Humans
Molecular Dynamics Simulation
Computer Simulation
Pyrazoles chemistry
Pyrazoles pharmacology
Quantitative Structure-Activity Relationship
Receptors, Cytoplasmic and Nuclear antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear chemistry
Receptors, Cytoplasmic and Nuclear metabolism
Amides chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0534
- Volume :
- 180
- Database :
- MEDLINE
- Journal :
- Computers in biology and medicine
- Publication Type :
- Academic Journal
- Accession number :
- 39126787
- Full Text :
- https://doi.org/10.1016/j.compbiomed.2024.108991