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Activity cliffs in PubChem confirmatory bioassays taking inactive compounds into account.
MedLine Citation:
PMID:  23296990     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Activity cliffs are formed by pairs or groups of structurally similar compounds with significant differences in potency. They represent a prominent feature of activity landscapes of compound data sets and a primary source of structure-activity relationship (SAR) information. Thus far, activity cliffs have only been considered for active compounds, consistent with the principles of the activity landscape concept. However, from an SAR perspective, pairs formed by structurally similar active and inactive compounds should often also be informative. Therefore, we have extended the activity cliff concept to also take inactive compounds into consideration. As source of both confirmed active and inactive compounds, we have exclusively focused on PubChem confirmatory bioassays. Activity cliffs formed between pairs of active compounds (homogeneous pairs) and pairs of active and inactive compounds (heterogeneous pairs) were systematically analyzed on a per-assay basis, hence ensuring the currently highest possible degree of experimental consistency in activity measurement. Only very small numbers of large-magnitude activity cliffs formed between active compounds were detected in PubChem bioassays. However, when taking confirmed inactive compounds from confirmatory assays into account, the activity cliff frequency in assay data significantly increased, involving 11-15 % of all qualifying pairs of similar compounds, depending on the molecular representations that were used. Hence, these non-conventional activity cliffs provide an additional source of SAR information.
Authors:
Ye Hu; Gerald M Maggiora; Jürgen Bajorath
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-8
Journal Detail:
Title:  Journal of computer-aided molecular design     Volume:  -     ISSN:  1573-4951     ISO Abbreviation:  J. Comput. Aided Mol. Des.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8710425     Medline TA:  J Comput Aided Mol Des     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, 53113, Bonn, Germany.
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