A Screening Pattern Recognition Method Finds New and Divergent Targets for Drugs and Natural Products
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- 作者：Anne Mai Wassermann ; Eugen Lounkine ; Laszlo Urban ; Steven Whitebread ; Shanni Chen ; Kevin Hughes ; Hongqiu Guo ; Elena Kutlina ; Alexander Fekete ; Martin Klumpp ; Meir Glick
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：July 18, 2014
- 年：2014
- 卷：9
- 期：7
- 页码：1622-1631
- 全文大小：468K
- ISSN：1554-8937
文摘
Computational target prediction methods using chemical descriptors have been applied exhaustively in drug discovery to elucidate the mechanisms-of-action (MOAs) of small molecules. To predict truly novel and unexpected small molecule鈥搕arget interactions, compounds must be compared by means other than their chemical structure alone. Here we investigated predictions made by a method, HTS fingerprints (HTSFPs), that matches patterns of activities in experimental screens. Over 1,400 drugs and 1,300 natural products (NPs) were screened in more than 200 diverse assays, creating encodable activity patterns. The comparison of these activity patterns to an MOA-annotated reference panel led to the prediction of 5,281 and 2,798 previously unknown targets for the NP and drug sets, respectively. Intriguingly, there was limited overlap among the targets predicted; the drugs were more biased toward membrane receptors and the NPs toward soluble enzymes, consistent with the idea that they represent unexplored pharmacologies. Importantly, HTSFPs inferred targets that were beyond the prediction capabilities of standard chemical descriptors, especially for NPs but also for the more explored drug set. Of 65 drug鈥搕arget predictions that we tested in vitro, 48 (73.8%) were confirmed with AC50 values ranging from 38 nM to 29 渭M. Among these interactions was the inhibition of cyclooxygenases 1 and 2 by the HIV protease inhibitor Tipranavir. These newly discovered targets that are phylogenetically and phylochemically distant to the primary target provide an explanation for spontaneous bleeding events observed for patients treated with this drug, a physiological effect that was previously difficult to reconcile with the drug鈥檚 known MOA.