title: A flexible approach to induced fit docking.
abstract: We present Fleksy, a new approach to consider both ligand and receptor flexibility in small molecule docking. Pivotal to our method is the use of a receptor ensemble to describe protein flexibility. To construct these ensembles, we use a backbone-dependent rotamer library and implement the concept of interaction sampling. The latter allows the evaluation of different orientations of ambivalent interaction partners. The docking stage consists of an ensemble-based soft-docking experiment using FlexX-Ensemble, followed by an effective flexible receptor-ligand complex optimization using Yasara. Fleksy produces a set of receptor-ligand complexes ranked using a consensus scoring function combining docking scores and force field energies. Averaged over three cross-docking datasets, containing 35 different receptor-ligand complexes in total, Fleksy reproduces the observed binding mode within 2.0 A for 78% of the complexes. This compares favorably to the rigid receptor FlexX program, which on average reaches a success rate of 44% for these datasets.
authors.affiliation: Center for Molecular and Biomolecular Informatics, Radboud University, Nijmegen, The Netherlands. sander@nabuurs.org
authors.forename: Sander B
authors.initials: SB
authors.lastname: Nabuurs
authors.forename: Markus
authors.initials: M
authors.lastname: Wagener
authors.forename: Jacob
authors.initials: J
authors.lastname: de Vlieg
mesh_terms: D001665:Binding Sites; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D018161:Receptors, Mineralocorticoid / Q000737:chemistry
chemical_list: D008024:Ligands; D011506:Proteins; D018161:Receptors, Mineralocorticoid; D017868:Cyclic AMP-Dependent Protein Kinases