Document Detail


Theoretical and Experimental Relationships between Percent Inhibition and IC50 Data Observed in High-Throughput Screening.
MedLine Citation:
PMID:  22853931     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The four-parameter logistic Hill equation models the theoretical relationship between inhibitor concentration and response and is used to derive IC(50) values as a measure of compound potency. This relationship is the basis for screening strategies that first measure percent inhibition at a single, uniform concentration and then determine IC(50) values for compounds above a threshold. In screening practice, however, a "good" correlation between percent inhibition values and IC(50) values is not always observed, and in the literature, there seems confusion about what correlation even to expect. We examined the relationship between percent inhibition data and IC(50) data in HDAC4 and ENPP2 high-throughput screening (HTS) data sets and compared our findings with a series of numerical simulations that allowed the investigation of the influence of parameters representing different types of uncertainties: variability in the screening concentration (related to solution library and compound characteristics, liquid handling), variations in Hill model parameters (related to interaction of compounds with target, type of assay), and influences of assay data quality parameters (related to assay and experimental design, liquid handling). In the different sensitivity analyses, we found that the typical variations of the actual compound concentrations in existing screening libraries generate the largest contributions to imperfect correlations. Excess variability in the ENPP2 assay above the values of the simulation model can be explained by compound aggregation artifacts.
Authors:
Hanspeter Gubler; Ulrich Schopfer; Edgar Jacoby
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-1
Journal Detail:
Title:  Journal of biomolecular screening     Volume:  -     ISSN:  1552-454X     ISO Abbreviation:  J Biomol Screen     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9612112     Medline TA:  J Biomol Screen     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1Informatics and Technology, Novartis Pharma AG, Institutes for BioMedical Research, Basel, Switzerland.
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