title: Challenges of docking in large, flexible and promiscuous binding sites.
abstract: After decades of work, the correct determination of the binding mode of a small molecule into a target protein is still a challenging problem, whose difficulty depends on: (i) the sizes of the binding site and the ligand; (ii) the flexibility of both interacting partners, and (iii) the differential solvation of bound and unbound partners. We have evaluated the performance of standard rigid(receptor)/flexible(ligand) docking approaches with respect to last-generation fully flexible docking methods to obtain reasonable poses in a very challenging case: soluble Epoxide Hydrolase (sEH), a flexible protein showing different binding sites. We found that full description of the flexibility of both protein and ligand and accurate description of solvation leads to significant improvement in the ability of docking to reproduce well known binding modes, and at the same time capture the intrinsic binding promiscuity of the protein.
authors.affiliation: Joint BSC-IRB Program in Computational Biology. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
authors.forename: Martin
authors.initials: M
authors.lastname: Kotev
authors.affiliation: Joint BSC-IRB Program in Computational Biology, Barcelona Supercomputing Center, Barcelona 08031, Spain.
authors.forename: Robert
authors.initials: R
authors.lastname: Soliva
authors.affiliation: Joint BSC-IRB Program in Computational Biology. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona (UB), Barcelona 08029, Spain. Electronic address: modesto.orozco@irbbarcelona.org.
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
mesh_terms: D001665:Binding Sites; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries; D004851:Epoxide Hydrolases
keywords: Benchmark; Induced-fit docking; PELE simulations; Soluble Epoxide Hydrolase