{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T06:12:07Z","timestamp":1774764727458,"version":"3.50.1"},"reference-count":78,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Hubei Province","award":["2023AFB102"],"award-info":[{"award-number":["2023AFB102"]}]},{"name":"Natural Science Foundation of Hubei Province","award":["OHIC2021Y02"],"award-info":[{"award-number":["OHIC2021Y02"]}]},{"name":"the Hubei Province Key Laboratory of Occupational Hazard Identification and Control","award":["2023AFB102"],"award-info":[{"award-number":["2023AFB102"]}]},{"name":"the Hubei Province Key Laboratory of Occupational Hazard Identification and Control","award":["OHIC2021Y02"],"award-info":[{"award-number":["OHIC2021Y02"]}]},{"name":"Wuhan University of Science and Technology","award":["2023AFB102"],"award-info":[{"award-number":["2023AFB102"]}]},{"name":"Wuhan University of Science and Technology","award":["OHIC2021Y02"],"award-info":[{"award-number":["OHIC2021Y02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The farnesoid X receptor (FXR) has been recognized as a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). FXR agonists benefit NAFLD by modulating bile acid synthesis and transport, lipid metabolism, inflammation, and fibrosis pathways. However, there are still great challenges involved in developing safe and effective FXR agonists. To investigate the critical factors contributing to their activity on the FXR, 3D-QSAR molecular modeling was applied to a series of isoxazole derivatives, using comparative molecular field analysis (CoMFA (q2 = 0.664, r2 = 0.960, r2pred = 0.872)) and comparative molecular similarity indices analysis (CoMSIA (q2 = 0.706, r2 = 0.969, r2pred = 0.866)) models, which demonstrated strong predictive ability in our study. The contour maps generated from molecular modeling showed that the presence of hydrophobicity at the R2 group and electronegativity group at the R3 group in these compounds is crucial to their agonistic activity. A molecular dynamics (MD) simulation was carried out to further understand the binding modes and interactions between the FXR and its agonists in preclinical or clinical studies. The conformational motions of loops L: H1\/H2 and L: H5\/H6 in FXR\u2013ligand binding domain (LBD) were crucial to the protein stability and agonistic activity of ligands. Hydrophobic interactions were formed between residues (such as LEU287, MET290, ALA291, HIS294, and VAL297) in helix H3 and ligands. In particular, our study found that residue ARG331 participated in salt bridges, and HIS447 participated in salt bridges and hydrogen bonds with ligands; these interactions were significant to protein\u2013ligand binding. Eight new potent FXR agonists were designed according to our results, and their activities were predicted to be better than that of the first synthetic FXR agonist, GW4064.<\/jats:p>","DOI":"10.3390\/molecules29061210","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T05:44:06Z","timestamp":1709876646000},"page":"1210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1424-1625","authenticated-orcid":false,"given":"Dan","family":"Yan","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueying","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanxiao","family":"Shen","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-4011","authenticated-orcid":false,"given":"Zhen","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Yao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eaaz2841","DOI":"10.1126\/scitranslmed.aaz2841","article-title":"Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome","volume":"12","author":"Rom","year":"2020","journal-title":"Sci. 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