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Rational design of FXR agonists: a computational approach for NASH therapy

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome, posing risks to cardiovascular and hepatic health worldwide. Non-alcoholic steatohepatitis (NASH) which is a severe form of NAFLD, has a global prevalence. Therapeutic targets for NASH include THR-β, GLP-1 receptor, PPARα/δ/γ, FGF21 analogs, and FXR, a bile acid nuclear receptor pivotal for regulating bile acid synthesis and excretion. Our study aims to design the non-steroidal FXR agonist for NASH treatment, as FXR’s role in the regulation of bile acid processes, rendering it a promising drug target for NASH therapy. Utilizing tropifexor as a reference molecule, we generated a shape-based pharmacophore model with seven features, identifying key binding requirements within the FXR active site. Virtual screening using this model, coupled with molecular docking studies, helped pinpoint potential ligands from diverse small molecule databases. Further analysis via MM/GBSA revealed 12 molecules with binding affinities comparable to tropifexor. Among them, DB15416 exhibited the lowest binding free energy and superior docking scores. To assess its dynamic stability, we subjected DB15416 to molecular dynamics simulations, confirming its suitability as a FXR agonist. These findings suggest that DB15416 holds promise as a FXR agonist for NASH treatment, which can be evaluated by experimental studies.

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Acknowledgements

The authors thank to the Director, National Institute of Pharmaceutical Education and Research (NIPER) SAS Nagar, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, New Delhi, Government of India for providing the provision to work.

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This project was not funded from any organization.

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  1. Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 166062, India

    Akshata Gandhe, Sonia Kumari & Masilamani Elizabeth Sobhia

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  1. Akshata Gandhe
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  2. Sonia Kumari
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  3. Masilamani Elizabeth Sobhia
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The concept of the study has been designed by the MES. The data collection and study were performed by AG. The manuscript was written by AG and corrected by SK. All authors have thoroughly reviewed the manuscript.

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Correspondence to Masilamani Elizabeth Sobhia.

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Gandhe, A., Kumari, S. & Elizabeth Sobhia, M. Rational design of FXR agonists: a computational approach for NASH therapy. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10766-9

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