Ranking docking poses by graph matching of protein–ligand interactions: lessons learned from the D3R Grand Challenge 2
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A novel docking challenge has been set by the Drug Design Data Resource (D3R) in order to predict the pose and affinity ranking of a set of Farnesoid X receptor (FXR) agonists, prior to the public release of their bound X-ray structures and potencies. In a first phase, 36 agonists were docked to 26 Protein Data Bank (PDB) structures of the FXR receptor, and next rescored using the in-house developed GRIM method. GRIM aligns protein–ligand interaction patterns of docked poses to those of available PDB templates for the target protein, and rescore poses by a graph matching method. In agreement with results obtained during the previous 2015 docking challenge, we clearly show that GRIM rescoring improves the overall quality of top-ranked poses by prioritizing interaction patterns already visited in the PDB. Importantly, this challenge enables us to refine the applicability domain of the method by better defining the conditions of its success. We notably show that rescoring apolar ligands in hydrophobic pockets leads to frequent GRIM failures. In the second phase, 102 FXR agonists were ranked by decreasing affinity according to the Gibbs free energy of the corresponding GRIM-selected poses, computed by the HYDE scoring function. Interestingly, this fast and simple rescoring scheme provided the third most accurate ranking method among 57 contributions. Although the obtained ranking is still unsuitable for hit to lead optimization, the GRIM–HYDE scoring scheme is accurate and fast enough to post-process virtual screening data.
KeywordsDocking D3R Drug discovery data resource Grand Challenge
We thank the CAPES foundation and the Ministry of Education of Brazil for a postdoctoral fellowship to P.S.F.C.G (Computational Biology program Grant, Issue No. 51/2013). The Computing Center of the IN2P3 (CNRS, Villeurbanne, France) is acknowledged for allocation of computing time and excellent support.
- 6.Community Structure Activity resource. http://www.csardock.org. Accessed 30 July 2010
- 7.Drug Design Data Resource. https://drugdesigndata.org/about/grand-challenge-2. Accessed 30 July 2010
- 13.Gathiaka S, Liu S, Chiu M, Yang H, Stuckey JA, Kang YN, Delproposto J, Kubish G, Dunbar JB Jr, Carlson HA, Burley SK, Walters WP, Amaro RE, Feher VA, Gilson MK (2016) D3R Grand Challenge 2015: evaluation of protein-ligand pose and affinity predictions. J Comput Aided Mol Des 30:651–668CrossRefGoogle Scholar
- 14.Smith RD, Damm-Ganamet KL, Dunbar JB Jr, Ahmed A, Chinnaswamy K, Delproposto JE, Kubish GM, Tinberg CE, Khare SD, Dou J, Doyle L, Stuckey JA, Baker D, Carlson HA (2016) CSAR benchmark exercise 2013: evaluation of results from a combined computational protein design, docking, and scoring/ranking challenge. J Chem Inf Model 56:1022–1031CrossRefGoogle Scholar
- 17.Richter HG, Benson GM, Bleicher KH, Blum D, Chaput E, Clemann N, Feng S, Gardes C, Grether U, Hartman P, Kuhn B, Martin RE, Plancher JM, Rudolph MG, Schuler F, Taylor S (2011) Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties. Bioorg Med Chem Lett 21:1134–1140CrossRefGoogle Scholar
- 18.Bass JY, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Mills WY, Navas F 3rd, Parks DJ, Smalley TL Jr, Spearing PK, Todd D, Williams SP, Wisely GB (2011) Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene. Bioorg Med Chem Lett 21:1206–1213CrossRefGoogle Scholar
- 22.Desaphy J, Da Silva F, Rognan D (2014) IChem v.5.2.6. http://bioinfo-pharma.u-strasbg.fr/labwebsite/downloads.
- 24.Xu X, Xu X, Liu P, Zhu ZY, Chen J, Fu HA, Chen LL, Hu LH, Shen X (2015) Structural basis for small molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a selective antagonist of farnesoid X receptor alpha (FXRalpha) in stabilizing the homodimerization of the receptor. J Biol Chem 290:19888–19899CrossRefGoogle Scholar
- 25.Jin L, Feng X, Rong H, Pan Z, Inaba Yu, Qiu L, Zheng W, Lin S, Wang R, Wang Z, Wang S, Liu H, Li S, Xie W, Li Y (2013) The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nat Commun 4:1937Google Scholar