title: Off-rate screening (ORS) by surface plasmon resonance. An efficient method to kinetically sample hit to lead chemical space from unpurified reaction products.
abstract: The dissociation rate constant kd (off-rate) is the component of ligand-protein binding with the most significant potential to enhance compound potency. Here we provide theoretical and empirical data to show that this parameter can be determined accurately from unpurified reaction products containing designed test compounds. This screening protocol is amenable to parallel chemistry, provides efficiencies of time and materials, and complements existing methodologies for the hit-to-lead phase in fragment-based drug discovery.
authors: Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
authors: James B
authors: JB
authors: Murray
authors: Stephen D
authors: SD
authors: Roughley
authors: Natalia
authors: N
authors: Matassova
authors: Paul A
authors: PA
authors: Brough
mesh_terms: D015374:Biosensing Techniques; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000302:isolation & purification*; D054852:Small Molecule Libraries / Q000737:chemistry*; D020349:Surface Plasmon Resonance / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries