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 GRIMselected 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.
Ranking docking poses by graph matching of protein–ligand interactions: lessons learned from the D3R Grand Challenge 2
Posted by
Guillaume Bret
on 12 09 2019
Related content
03 10 2022
< 1 minute
Calculate on the cloud
In order to increase the flexibility, access and integrability, Calculators and Predictors have...
12 05 2022
< 1 minute
Coupling stabilizers open KV1-type potassium channels
ABSTRACT: The opening and closing of voltage-gated ion channels are regulated by voltage sensors...
13 11 2021
< 1 minute
Cheminfo Stories 2021 Virtual UGM | Boost analytical experiments with phys-chem properties
TRY CHEMICALIZE Log in for videos & slides
13 11 2021
< 1 minute
Cheminfo Stories 2021 Virtual UGM | Enhancing Sibylla’s innovative drug discovery platform with ChemAxon
Sibylla's innovative pharmacological platform is aimed at discovering new drugs for untreatable...