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ACS Chem Biol. 2015 Apr 17;10(4):978-88. doi: 10.1021/cb5009487. Epub 2015 Feb 9.

Colloidal aggregation and the in vitro activity of traditional Chinese medicines.

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†Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 Fourth Street, San Francisco, California 94158-2550, United States.
‡Leslie Dan Faculty of Pharmacy, Donnelly Center, University of Toronto, 144 College Street, Toronto, Ontario M5S3M2, Canada.


Traditional Chinese Medicines (TCMs) have been the sole source of therapeutics in China for two millennia. In recent drug discovery efforts, purified components of TCM formulations have shown activity in many in vitro assays, raising concerns of promiscuity. Here, we investigated 14 bioactive small molecules isolated from TCMs for colloidal aggregation. At concentrations commonly used in cell-based or biochemical assay conditions, eight of these compounds formed particles detectable by dynamic light scattering and showed detergent-reversible inhibition against β-lactamase and malate dehydrogenase, two counter-screening enzymes. When three of these compounds were tested against their literature-reported molecular targets, they showed similar reversal of their inhibitory activity in the presence of detergent. For three of the most potent aggregators, contributions to promiscuity via oxidative cycling were investigated; addition of 1 mM DTT had no effect on their activity, which is inconsistent with an oxidative mechanism. TCMs are often active at micromolar concentrations; this study suggests that care must be taken to control for artifactual activity when seeking their primary targets. Implications for the formulation of these molecules are considered.

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