Dynamic undocking and the quasi-bound state as tools for drug discovery

TY - JOUR

T1 - Dynamic undocking and the quasi-bound state as tools for drug discovery

AU - Sergio, Ruiz-Carmona

AU - Schmidtke, Peter

AU - Luque, F. Javier

AU - Baker, Lisa

AU - Matassova, Natalia

AU - Davis, Ben

AU - Roughley, Stephen

AU - Murray, James

AU - Hubbard, Roderick Eliot

AU - Barril, Xavier

N1 - © 2016 Macmillan Publishers Limited. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details

PY - 2017/3/1

Y1 - 2017/3/1

N2 - There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein–ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important nativecontact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other ‘thermodynamic’ methods. We demonstrate the potential of the docking–undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%

AB - There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein–ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important nativecontact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other ‘thermodynamic’ methods. We demonstrate the potential of the docking–undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%

UR - http://www.scopus.com/inward/record.url?scp=85013853067&partnerID=8YFLogxK

U2 - 10.1038/nchem.2660

DO - 10.1038/nchem.2660

M3 - Article

SN - 1755-4330

VL - 9

SP - 201

EP - 206

JO - Nature Chemistry

JF - Nature Chemistry

IS - 3

ER -