title: Dynamic undocking and the quasi-bound state as tools for drug discovery.
abstract: 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 native contact 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%.
authors.affiliation: Institut de Biomedicina de la Universitat de Barcelona (IBUB) and Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz-Carmona
authors.affiliation: Discngine, 33 rue du Fauburg Saint-Antoine, 75011 Paris, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidtke
authors.affiliation: Institut de Biomedicina de la Universitat de Barcelona (IBUB) and Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Baker
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Matassova
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Davis
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.
authors.forename: Stephen
authors.identifier: 0000-0003-0683-5693
authors.initials: S
authors.lastname: Roughley
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.
authors.forename: James
authors.initials: J
authors.lastname: Murray
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.|YSBL, University of York, Heslington, York YO10 5DD, UK.
authors.forename: Rod
authors.initials: R
authors.lastname: Hubbard
authors.affiliation: Institut de Biomedicina de la Universitat de Barcelona (IBUB) and Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.|Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Xavier
authors.identifier: 0000-0002-0281-1347
authors.initials: X
authors.lastname: Barril
mesh_terms: D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D004364:Pharmaceutical Preparations