Docking pose selection by interaction pattern graph similarity: application to the D3R grand challenge 2015

• Published in: Journal of computer-aided molecular design Vol. 30; no. 9; pp. 669 - 683
• Main Authors: Slynko, Inna, Da Silva, Franck, Bret, Guillaume, Rognan, Didier
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2016; Springer Nature B.V; Springer Verlag
• Subjects: Amino acids; Animal Anatomy; Binding Sites; Chemical Sciences; Cheminformatics; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Crystallography, X-Ray; Docking; Graphs; Histology; Inhibitors; Ligands; Mathematical analysis; Mathematical models; Models, Molecular; Molecular biology; Molecular Docking Simulation; Morphology; Physical Chemistry; Protein Binding; Protein Conformation; Proteins - chemistry; Scoring; Thermodynamics; X-rays; Grand challenge; Docking; D3R; Drug discovery data resource
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-016-9930-3

High affinity ligands for a given target tend to share key molecular interactions with important anchoring amino acids and therefore often present quite conserved interaction patterns. This simple concept was formalized in a topological knowledge-based scoring function (GRIM) for selecting the most appropriate docking poses from previously X-rayed interaction patterns. GRIM first converts protein–ligand atomic coordinates (docking poses) into a simple 3D graph describing the corresponding interaction pattern. In a second step, proposed graphs are compared to that found from template structures in the Protein Data Bank. Last, all docking poses are rescored according to an empirical score (GRIMscore) accounting for overlap of maximum common subgraphs. Taking the opportunity of the public D3R Grand Challenge 2015, GRIM was used to rescore docking poses for 36 ligands (6 HSP90α inhibitors, 30 MAP4K4 inhibitors) prior to the release of the corresponding protein–ligand X-ray structures. When applied to the HSP90α dataset, for which many protein–ligand X-ray structures are already available, GRIM provided very high quality solutions (mean rmsd = 1.06 Å, n = 6) as top-ranked poses, and significantly outperformed a state-of-the-art scoring function. In the case of MAP4K4 inhibitors, for which preexisting 3D knowledge is scarce and chemical diversity is much larger, the accuracy of GRIM poses decays (mean rmsd = 3.18 Å, n = 30) although GRIM still outperforms an energy-based scoring function. GRIM rescoring appears to be quite robust with comparison to the other approaches competing for the same challenge (42 submissions for the HSP90 dataset, 27 for the MAP4K4 dataset) as it ranked 3rd and 2nd respectively, for the two investigated datasets. The rescoring method is quite simple to implement, independent on a docking engine, and applicable to any target for which at least one holo X-ray structure is available.