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Schorpp, K.K. ; Rothenaigner, I. ; Salmina, E. ; Reinshagen, J.* ; Low, T.* ; Brenke, J.K. ; Gopalakrishnan, J.* ; Tetko, I.V. ; Gul, S.* ; Hadian, K.

Identification of small-molecule frequent hitters from AlphaScreen high-throughput screens.

J. Biomol. Screen. 19, 715-726 (2013)
Verlagsversion Volltext DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Although small-molecule drug discovery efforts have focused largely on enzyme, receptor, and ion-channel targets, there has been an increase in such activities to search for protein-protein interaction (PPI) disruptors by applying high-throughout screening (HTS)-compatible protein-binding assays. However, a disadvantage of these assays is that many primary hits are frequent hitters regardless of the PPI being investigated. We have used the AlphaScreen technology to screen four different robust PPI assays each against 25,000 compounds. These activities led to the identification of 137 compounds that demonstrated repeated activity in all PPI assays. These compounds were subsequently evaluated in two AlphaScreen counter assays, leading to classification of compounds that either interfered with the AlphaScreen chemistry (60 compounds) or prevented the binding of the protein His-tag moiety to nickel chelate (Ni(2+)-NTA) beads of the AlphaScreen detection system (77 compounds). To further triage the 137 frequent hitters, we subsequently confirmed by a time-resolved fluorescence resonance energy transfer assay that most of these compounds were only frequent hitters in AlphaScreen assays. A chemoinformatics analysis of the apparent hits provided details of the compounds that can be flagged as frequent hitters of the AlphaScreen technology, and these data have broad applicability for users of these detection technologies.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Alphascreen ; Protein-protein Interaction ; Assay Development ; Frequent Hitter ; Drug Discovery ; High-throughput Screening; Protein-protein Interactions; Drug Discovery; Solubility; Chemistry; Libraries; Fragment; Filters; Models; Domain
ISSN (print) / ISBN 1087-0571
e-ISSN 1552-454X
Zeitschrift Journal of Biomolecular Screening
Quellenangaben Band: 19, Heft: 5, Seiten: 715-726 Artikelnummer: , Supplement: ,
Verlag Sage
Verlagsort Thousand Oaks
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Structural Biology (STB)