title: Repositioning the substrate activity screening (SAS) approach as a fragment-based method for identification of weak binders.
abstract: Fragment-based drug discovery (FBDD) has evolved into an established approach for "hit" identification. Typically, most applications of FBDD depend on specialised cost- and time-intensive biophysical techniques. The substrate activity screening (SAS) approach has been proposed as a relatively cheap and straightforward alternative for identification of fragments for enzyme inhibitors. We have investigated SAS for the discovery of inhibitors of oncology target urokinase (uPA). Although our results support the key hypotheses of SAS, we also encountered a number of unreported limitations. In response, we propose an efficient modified methodology: "MSAS" (modified substrate activity screening). MSAS circumvents the limitations of SAS and broadens its scope by providing additional fragments and more coherent SAR data. As well as presenting and validating MSAS, this study expands existing SAR knowledge for the S1 pocket of uPA and reports new reversible and irreversible uPA inhibitor scaffolds.
authors.affiliation: Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk (Belgium).
authors.forename: Rafaela
authors.initials: R
authors.lastname: Gladysz
authors.forename: Matthias
authors.initials: M
authors.lastname: Cleenewerck
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
mesh_terms: D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D058492:Drug Repositioning; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014568:Urokinase-Type Plasminogen Activator
keywords: MSAS; SAS; drug design; inhibitors; urokinase