title: Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors.
abstract: Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC50's ∼500μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4μM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization.
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA. Electronic address: jeffrey.varnes@astrazeneca.com.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Varnes
authors.affiliation: Discovery Sciences, AstraZeneca R&D, SE-431 83 Mölndal, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Geschwindner
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Holmquist
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Forst
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Discovery Sciences, AstraZeneca R&D, SE-431 83 Mölndal, Sweden.
authors.forename: Niek
authors.initials: N
authors.lastname: Dekker
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA.
authors.forename: Clay W
authors.initials: CW
authors.lastname: Scott
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA.
authors.forename: Gaochao
authors.initials: G
authors.lastname: Tian
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wood
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA. Electronic address: jeffrey.albert@intellisynrd.com.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Albert
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Fragment-assisted drug discovery; Fragment-based drug discovery; PDE10A; Phosphodiesterase inhibitor; Schizophrenia