Blinded Evaluation of Farnesoid X Receptor (FXR) Ligands Binding Using Molecular Docking and Free Energy Calculations

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2017 Sep 3

PMID 28865056

Citations 4

Authors

Edithe Selwa

Eddy Elisee

Agustin Zavala

Bogdan I Iorga

Affiliations

Soon will be listed here.

Abstract

Our participation to the D3R Grand Challenge 2 involved a protocol in two steps, with an initial analysis of the available structural data from the PDB allowing the selection of the most appropriate combination of docking software and scoring function. Subsequent docking calculations showed that the pose prediction can be carried out with a certain precision, but this is dependent on the specific nature of the ligands. The correct ranking of docking poses is still a problem and cannot be successful in the absence of good pose predictions. Our free energy calculations on two different subsets provided contrasted results, which might have the origin in non-optimal force field parameters associated with the sulfonamide chemical moiety.

Citing Articles

D3R grand challenge 4: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies.

Parks C, Gaieb Z, Chiu M, Yang H, Shao C, Walters W J Comput Aided Mol Des. 2020; 34(2):99-119.

PMID: 31974851 PMC: 7261493. DOI: 10.1007/s10822-020-00289-y.

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset.

Elisee E, Gapsys V, Mele N, Chaput L, Selwa E, de Groot B J Comput Aided Mol Des. 2019; 33(12):1031-1043.

PMID: 31677003 DOI: 10.1007/s10822-019-00232-w.

Blinded evaluation of cathepsin S inhibitors from the D3RGC3 dataset using molecular docking and free energy calculations.

Chaput L, Selwa E, Elisee E, Iorga B J Comput Aided Mol Des. 2018; 33(1):93-103.

PMID: 30206740 DOI: 10.1007/s10822-018-0161-7.

Hybrid receptor structure/ligand-based docking and activity prediction in ICM: development and evaluation in D3R Grand Challenge 3.

Lam P, Abagyan R, Totrov M J Comput Aided Mol Des. 2018; 33(1):35-46.

PMID: 30094533 DOI: 10.1007/s10822-018-0139-5.

References

Adorini L, Pruzanski M, Shapiro D . Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today. 2012; 17(17-18):988-97. DOI: 10.1016/j.drudis.2012.05.012. View

Sepe V, Distrutti E, Limongelli V, Fiorucci S, Zampella A . Steroidal scaffolds as FXR and GPBAR1 ligands: from chemistry to therapeutical application. Future Med Chem. 2015; 7(9):1109-35. DOI: 10.4155/fmc.15.54. View

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

Sepe V, Distrutti E, Fiorucci S, Zampella A . Farnesoid X receptor modulators (2011 - 2014): a patent review. Expert Opin Ther Pat. 2015; 25(8):885-96. DOI: 10.1517/13543776.2015.1045413. View

Pellicciari R, Costantino G, Fiorucci S . Farnesoid X receptor: from structure to potential clinical applications. J Med Chem. 2005; 48(17):5383-403. DOI: 10.1021/jm0582221. View

Pronk S, Pall S, Schulz R, Larsson P, Bjelkmar P, Apostolov R . GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013; 29(7):845-54. PMC: 3605599. DOI: 10.1093/bioinformatics/btt055. View

Gege C, Kinzel O, Steeneck C, Schulz A, Kremoser C . Knocking on FXR's door: the "hammerhead"-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities. Curr Top Med Chem. 2014; 14(19):2143-58. DOI: 10.2174/1568026614666141112094430. View

Sanyal A . Use of farnesoid X receptor agonists to treat nonalcoholic fatty liver disease. Dig Dis. 2015; 33(3):426-32. DOI: 10.1159/000371698. View

Claudel T, Sturm E, Kuipers F, Staels B . The farnesoid X receptor: a novel drug target?. Expert Opin Investig Drugs. 2004; 13(9):1135-48. DOI: 10.1517/13543784.13.9.1135. View

10.

Richter H, Benson G, Bleicher K, Blum D, Chaput E, Clemann N . Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties. Bioorg Med Chem Lett. 2011; 21(4):1134-40. DOI: 10.1016/j.bmcl.2010.12.123. View

11.

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

12.

Alawad A, Levy C . FXR Agonists: From Bench to Bedside, a Guide for Clinicians. Dig Dis Sci. 2016; 61(12):3395-3404. DOI: 10.1007/s10620-016-4334-8. View

13.

Cariou B, Staels B . FXR: a promising target for the metabolic syndrome?. Trends Pharmacol Sci. 2007; 28(5):236-43. DOI: 10.1016/j.tips.2007.03.002. View

14.

Feng S, Yang M, Zhang Z, Wang Z, Hong D, Richter H . Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist. Bioorg Med Chem Lett. 2009; 19(9):2595-8. DOI: 10.1016/j.bmcl.2009.03.008. View

15.

De Magalhaes Filho C, Downes M, Evans R . Farnesoid X Receptor an Emerging Target to Combat Obesity. Dig Dis. 2017; 35(3):185-190. PMC: 5417073. DOI: 10.1159/000450909. View

16.

Fiorucci S, Distrutti E, Ricci P, Giuliano V, Donini A, Baldelli F . Targeting FXR in cholestasis: hype or hope. Expert Opin Ther Targets. 2014; 18(12):1449-59. DOI: 10.1517/14728222.2014.956087. View

17.

Surpateanu G, Iorga B . Evaluation of docking performance in a blinded virtual screening of fragment-like trypsin inhibitors. J Comput Aided Mol Des. 2011; 26(5):595-601. DOI: 10.1007/s10822-011-9526-x. View

18.

Teodoro J, Rolo A, Palmeira C . Hepatic FXR: key regulator of whole-body energy metabolism. Trends Endocrinol Metab. 2011; 22(11):458-66. DOI: 10.1016/j.tem.2011.07.002. View

19.

Lamers C, Schubert-Zsilavecz M, Merk D . Medicinal chemistry and pharmacological effects of Farnesoid X Receptor (FXR) antagonists. Curr Top Med Chem. 2014; 14(19):2188-205. DOI: 10.2174/1568026614666141112103516. View

20.

Selwa E, Martiny V, Iorga B . Molecular docking performance evaluated on the D3R Grand Challenge 2015 drug-like ligand datasets. J Comput Aided Mol Des. 2016; 30(9):829-839. DOI: 10.1007/s10822-016-9983-3. View