Computational Insights into the Interactions of Farnesoid X Receptor with Fargesone A, a Natural Product from Magnolia fargesii

Abstract

Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor and plays important roles in the regulation of metabolism and homeostasis of several important physiological substances, such as bile acids, glucose, and lipids. As such, FXR has become a promising therapeutic target for the treatment of several metabolic diseases and liver disorders. Recently, fargesone A (FA), a natural product from Magnolia fargesii was identified to be a novel, potent FXR agonist that demonstrated good in vitro and in vivo activities. However, the detailed interaction mechanism of FA with FXR remains unclear. In this study, we employed multiple computational approaches including molecular docking, molecular dynamics simulation, and binding free energy calculation to address the issue. By comparisons of the structural dynamics and binding free energies, an optimal binding mode was identified, in which FA interacts with FXR via a direct hydrogen bond with His447 and hydrophobic interactions with multiple residues, such as Leu287, Met290, Met328, Ile352, and Trp454. Two mutants, namely, H447F and L287N, were further constructed to validate the importance of the identified residues. We anticipate that these findings could be helpful for future rational design of new FA analogues targeting FXR.

References

[[1]] Makishima M, Okamoto A Y, Repa J J, Tu H, Learned R M, Luk A, Hull M V, Lustig K D, Mangelsdorf D J, Shan B Science, 1999, 284: 1362.

[[2]] Parks D J, Blanchard S G, Bledsoe R K, Chandra G, Consler T G, Kliewer S A, Stimmel J B, Willson T M, Zavacki A M, Moore D D, Lehmann J M Science, 1999, 284: 1365.

[[3]] Wang H, Chen J, Hollister K, Sowers L C, Forman B Mol. Cell, 1999, 3: 543.

[[4]] Fiorucci S, Distrutti E, Carino A, Zampella A, Biagioli M Prog. Lipid Res., 2021, 82: 101094.

[[5]] Chiang J Y L J. Lipid Res., 2009, 50: 1955.

[[6]] Fiorucci S, Biagioli M, Baldoni M, Ricci P, Sepe V, Zampella A, Distrutti E Expert Opin. Drug Dis., 2021, 16: 1193.

[[7]] Panzitt K, Zollner G, Marschall H, Wagner M Mol. Cell. Endocrinol., 2022, 552: 111678.

[[8]] Adorini L, Trauner M J. Hepatol., 2023, 79: 1317.

[[9]] Fang Y, Hegazy L, Finck B N, Elgendy B J. Med. Chem., 2021, 64: 17545.

[[10]] Xu Y J. Med. Chem., 2016, 59: 6553.

[[11]] Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney P R, Morelli A, Parks D J, Willson T M J. Med. Chem., 2002, 45: 3569.

[[12]] Mullard A Nat. Rev. Drug Discov., 2020, 19: 501

[[13]] Yin Y, Wang M, Gu W, Chen L Biochem. Pharmacol., 2021, 186: 114430.

[[14]] Li Y, Xu T, Zhao Y, Zhang H, Liu Z, Wang H, Huang C, Shu Z, Gao L, Xie R, Jiao T, Zhang D, Zhang D, Liang X, Zang Y, Sun Y, Liu H, Li J, Zhou Y J. Med. Chem., 2024, 67: 5642.

[[15]] Guo F, Chen K, Dong H, Hu D, Gao Y, Liu C, Laphookhieo S, Lei X JACS Au, 2022, 2: 2830.

[[16]] Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker B A, Thiessen P A, Yu B, Zaslavsky L, Zhang J, Bolton E E Nucleic Acids Res., 2023, 51: D1373.

[[17]] Lu C, Wu C, Ghoreishi D, Chen W, Wang L, Damm W, Ross GA, Dahlgren M K, Russell E, Von Bargen C D, Abel R, Friesner R A, Harde E D J. Chem. Theory Comput., 2021, 17: 4291.

[[18]] Akwabi-Ameyaw A, Bass J Y, Caldwell R D, Caravella J A, Chen L, Creech K L, Deaton D N, Jones S A, Kaldor I, Liu Y, Madauss K P, Marr H B, McFadyen R B, Miller A B, Iii F N, Parks D J, Spearing P K, Todd D, Williams S P, Wisely G B Bioorg. Med. Chem. Lett., 2008, 18: 4339.

[[19]] Mi L, Devarakonda S, Harp J M, Han Q, Pellicciari R, Willson T M, Khorasanizadeh S, Rastinejad F Mol. Cell, 2003, 11: 1093.

[[20]] Merk D, Sreeramulu S, Kudlinzki D, Saxena K, Linhard V, Gande S L, Hiller F, Lamers C, Nilsson E, Aagaard A, Wissler L, Dekker N, Bamberg K, Schubert-Zsilavecz M, Schwalbe H Nat. Commun., 2019, 10: 2915.

[[21]] Friesner R A, Banks J L, Murphy R B, Halgren T A, Klicic J J, Mainz D T, Repasky M P, Knoll E H, Shelley M, Perry J K, Shaw D E, Francis P, Shenkin P S J. Med. Chem., 2004, 47: 1739.

[[22]] Case D A, Cheatham T E III, Darden T, Gohlke H, Luo R, Merz K M Jr., Onufriev A, Simmerling C, Wang B, Woods R J J. Comput. Chem., 2005, 26: 1668.

[[23]] Olsson M H, Sondergaard C R, Rostkowski M, Jensen J H J. Chem. Theory Comput., 2011, 7: 525.

[[24]] Wang J, Wolf R M, Caldwell J W, Kollman P A, Case D A J. Comput. Chem., 2004, 25: 1157.

[[25]] Maier J, Martinez C, Kasavajhala K, Wickstrom L, Hauser K, Simmerling C J. Chem. Theory Comput., 2015, 11: 3696.

[[26]] Jorgensen W L, Chandrasekhar J, Madura J D, Impey R, Klein M L J. Chem. Phys., 1983, 79: 926.

[[27]] Chen Y, Li J, Wu Z, Liu G, Li H, Tang Y, Li W J. Chem. Inf. Model., 2020, 60: 1540.

[[28]] Li W, Fu J, Cheng F, Zheng M, Zheng M, Zhang J, Liu G, Tang Y J. Chem. Inf. Model., 2012, 52: 3043.

[[29]] Ruymgaart A P, Hess B Eur. Phys. J.: Spec. Top., 2011, 200: 211

[[30]] Essmann U, Perera L, Berkowitz W L, Darden T, Lee H, Pedersen L G J. Chem. Phys., 1995, 103: 8577.

[[31]] Roe D R, Cheatham T E J. Chem. Theory Comput., 2013, 9: 3084.

[[32]] Genheden S, Ryde U Expert Opin. Drug Discov., 2015, 10: 449.

[[33]] Wang E, Sun H, Wang J, Wang Z, Liu H, Zhang J Z H, Hou T Chem. Rev., 2019, 119: 9478.

[[34]] Weiser J, Shenkin P S, Still W C J. Comput. Chem., 1999, 20: 217.

[[35]] Onufriev A, Bashford D, Case D A J. Phys. Chem. B, 2000, 104: 3712.

[[36]] Brooks B R, Janezic D, Karplus M J. Comput. Chem., 1995, 16: 1522.

[[37]] Yu Y, Wang Z, Wang L, Tian S, Hou T, Sun H J. Cheminform., 2022, 14: 56.

[[38]] Feng Y, Gong C, Zhu J, Liu G, Tang Y, Li W J. Chem. Inf. Model., 2024, 64: 3451.

[[39]] Adasme M F, Linnemann K L, Bolz S N, Kaiser F, Salentin S, Haupt V J, Schroeder M Nucleic Acids Res., 2021, 49: W530.

[[40]] De Vivo M, Masetti M, Bottegoni G, Cavalli A J. Med. Chem., 2016, 59: 4035.

[[41]] Sledz P., Caflisch A., Curr. Opin. Struct Biol., 2018, 93.

[[42]] Hang J, Lv L, Zhu H, Zhang Y, Xu X, Long L, Fu W Chem. Res. Chinese Universities, 2024, 40: 1201.

[[43]] Shen Q, Chen H, Gao D, Zhao X, Na R, Liu J, Huang X Chem. J. Chinese Universities, 2023, 44: 20220500

[[44]] Zhou M, Li Y Chem. Res. Chinese Universities, 2022, 38: 1400.