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Quantitative analyses of aggregation, autofluorescence, and reactivity artifacts in a screen for inhibitors of a thiol protease.

Abstract：

:The perceived and actual burden of false positives in high-throughput screening has received considerable attention; however, few studies exist on the contributions of distinct mechanisms of nonspecific effects like chemical reactivity, assay signal interference, and colloidal aggregation. Here, we analyze the outcome of a screen of 197861 diverse compounds in a concentration-response format against the cysteine protease cruzain, a target expected to be particularly sensitive to reactive compounds, and using an assay format with light detection in the short-wavelength region where significant compound autofluorescence is typically encountered. Approximately 1.9% of all compounds screened were detergent-sensitive inhibitors. The contribution from autofluorescence and compounds bearing reactive functionalities was dramatically lower: of all hits, only 1.8% were autofluorescent and 1.5% contained reactive or undesired functional groups. The distribution of false positives was relatively constant across library sources. The simple step of including detergent in the assay buffer suppressed the nonspecific effect of approximately 93% of the original hits.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Jadhav A,Ferreira RS,Klumpp C,Mott BT,Austin CP,Inglese J,Thomas CJ,Maloney DJ,Shoichet BK,Simeonov A

doi

10.1021/jm901070c

subject

Has Abstract

pub_date

2010-01-14 00:00:00

pages

37-51

issue

1

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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