Universität zu Köln

Schorpp, Kenji, Rothenaigner, Ina, Salmina, Elena ORCID: 0000-0002-3526-4378, Reinshagen, Jeanette, Low, Terence, Brenke, Jara K., Gopalakrishnan, Jay, Tetko, Igor V. ORCID: 0000-0002-6855-0012, Gul, Sheraz and Hadian, Kamyar ORCID: 0000-0001-8727-2575 (2014). Identification of Small-Molecule Frequent Hitters from AlphaScreen High-Throughput Screens. J. Biomol. Screen, 19 (5). S. 715 - 727. THOUSAND OAKS: SAGE PUBLICATIONS INC. ISSN 1552-454X

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Abstract

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 (Ni2+-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schorpp, Kenji UNSPECIFIED UNSPECIFIED UNSPECIFIED Rothenaigner, Ina UNSPECIFIED UNSPECIFIED UNSPECIFIED Salmina, Elena UNSPECIFIED orcid.org/0000-0002-3526-4378 UNSPECIFIED Reinshagen, Jeanette UNSPECIFIED UNSPECIFIED UNSPECIFIED Low, Terence UNSPECIFIED UNSPECIFIED UNSPECIFIED Brenke, Jara K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gopalakrishnan, Jay UNSPECIFIED UNSPECIFIED UNSPECIFIED Tetko, Igor V. UNSPECIFIED orcid.org/0000-0002-6855-0012 UNSPECIFIED Gul, Sheraz UNSPECIFIED UNSPECIFIED UNSPECIFIED Hadian, Kamyar UNSPECIFIED orcid.org/0000-0001-8727-2575 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-437515
DOI:	10.1177/1087057113516861
Journal or Publication Title:	J. Biomol. Screen
Volume:	19
Number:	5
Page Range:	S. 715 - 727
Date:	2014
Publisher:	SAGE PUBLICATIONS INC
Place of Publication:	THOUSAND OAKS
ISSN:	1552-454X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN-PROTEIN INTERACTIONS; DRUG DISCOVERY; SOLUBILITY; CHEMISTRY; LIBRARIES; FRAGMENT; FILTERS; MODELS; DOMAIN Multiple languages Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43751