title: Development of a plate-based optical biosensor fragment screening methodology to identify phosphodiesterase 10A inhibitors.
abstract: We describe the development of a novel fragment screening methodology employing a plate-based optical biosensor system that can operate in a 384-well format. The method is based on the "inhibition in solution assay" (ISA) approach using an immobilized target definition compound (TDC) that has been specifically designed for this purpose by making use of available structural information. We demonstrate that this method is robust and is sufficiently sensitive to detect fragment hits as weak as KD 500 μM when confirmed in a conventional surface plasmon resonance approach. The application of the plate-based screen, the identification of fragment inhibitors of PDE10A, and their structural characterization are all discussed in a forthcoming paper.
authors.affiliation: Discovery Sciences, AstraZeneca R&D Mölndal, S-43183 Mölndal, Sweden. Stefan.Geschwindner@astrazeneca.com
authors.forename: Stefan
authors.initials: S
authors.lastname: Geschwindner
authors.forename: Niek
authors.initials: N
authors.lastname: Dekker
authors.forename: Rob
authors.initials: R
authors.lastname: Horsefield
authors.forename: Anna
authors.initials: A
authors.lastname: Tigerström
authors.forename: Patrik
authors.initials: P
authors.lastname: Johansson
authors.forename: Clay W
authors.initials: CW
authors.lastname: Scott
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Albert
mesh_terms: D015374:Biosensing Techniques; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D010726:Phosphodiesterase Inhibitors / Q000302:isolation & purification*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D020349:Surface Plasmon Resonance
chemical_list: D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases