A Flexible Approach to Induced Fit Docking

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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 Å 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.