TY - JOUR
T1 - The Ecstasy and Agony of Assay Interference Compounds
AU - Aldrich, Courtney
AU - Bertozzi, Carolyn
AU - Georg, Gunda I.
AU - Kiessling, Laura
AU - Lindsley, Craig
AU - Liotta, Dennis
AU - Merz, Kenneth M.
AU - Schepartz, Alanna
AU - Wang, Shaomeng
PY - 2017/3/27
Y1 - 2017/3/27
N2 - The ecstasy of discovering a new hit from screening can lead to a highly productive research effort to discover new bioactive compounds. However, in too many cases this ecstasy is followed by the agony of realizing that the compounds are not active against the desired target. Many of these false hits are Pan Assay INterference compoundS (PAINS) or colloidal aggregators. Alarmingly, up to 80−100% of initial hits from screening can be artifacts if appropriate control experiments are not employed. Perhaps the largest single source of artifacts in early discovery is colloidal aggregation by small molecules. These particles, typically between 50 and 1000 nm in radius, nonspecifically adsorb protein, partially denaturing them. About two percent of molecules in a typical screening deck will aggregate at relevant concentrations, ensuring that hits reflecting colloid formation dominate in screens, both virtual and empirical, which do not control for them. Fortunately, molecules that act as aggregators can sometimes be recognized computationally and better still, this mechanism may be readily controlled experimentally.
AB - The ecstasy of discovering a new hit from screening can lead to a highly productive research effort to discover new bioactive compounds. However, in too many cases this ecstasy is followed by the agony of realizing that the compounds are not active against the desired target. Many of these false hits are Pan Assay INterference compoundS (PAINS) or colloidal aggregators. Alarmingly, up to 80−100% of initial hits from screening can be artifacts if appropriate control experiments are not employed. Perhaps the largest single source of artifacts in early discovery is colloidal aggregation by small molecules. These particles, typically between 50 and 1000 nm in radius, nonspecifically adsorb protein, partially denaturing them. About two percent of molecules in a typical screening deck will aggregate at relevant concentrations, ensuring that hits reflecting colloid formation dominate in screens, both virtual and empirical, which do not control for them. Fortunately, molecules that act as aggregators can sometimes be recognized computationally and better still, this mechanism may be readily controlled experimentally.
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U2 - 10.1021/acs.jcim.7b00105
DO - 10.1021/acs.jcim.7b00105
M3 - Review article
C2 - 28244743
AN - SCOPUS:85025074180
SN - 1549-9596
VL - 57
SP - 387
EP - 390
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 3
ER -