Title
Repositioning the Substrate Activity Screening (SAS) Approach as a Fragment-Based Method for Identification of Weak Binders Repositioning the Substrate Activity Screening (SAS) Approach as a Fragment-Based Method for Identification of Weak Binders
Author
Faculty/Department
Faculty of Sciences. Biology
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Weinheim :Wiley ,
Subject
Chemistry
Biology
Pharmacology. Therapy
Source (journal)
ChemBioChem: a European journal of chemical biology. - Weinheim
Volume/pages
15(2014) :15 , p. 2238-2247
ISSN
1439-4227
ISI
000342901800011
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
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