Michael J. Keiser, PhD                                                                               

SeaChange Pharmaceuticals, Inc.                     

Predicting unexpected off-targets for approved drugs

Chemically similar drugs often bind to molecular targets that are unrelated by sequence or by protein structure. Systems pharmacology networks organizing drugs and their targets could reveal links that molecular biology methods might otherwise miss. To investigate this assumption, we developed the Similarity Ensemble Approach, which compares known drugs against thousands of therapeutic targets. Hundreds of novel off-target drug activities consistent with adverse events, mechanisms of action, and new uses were predicted and confirmed in pharmacological assays. We have since extended these methods to prioritize testing for adverse drug reactions, and to predict the mechanism-of-action targets of compound actives found in phenotypic screens. The chemical similarity approach used here is systematic and comprehensive, and may find use for illuminating unexpected effects of approved drugs.

References

1. Lounkine E,* Keiser MJ,* Whitebread S, Mikhailov D, Hamon J, Jenkins J, Lavan P, Weber E, Doak AK, Côté S, Shoichet BK, Urban L. Large scale prediction and testing of drug activity on side-effect targets. Nature. 486 (7403), 361-7 (2012).

2. Keiser MJ,* Setola V,* Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, Matos RC, Tran TB, Whaley R, Glennon RA, Hert J, Thomas KLH, Edwards DD, Shoichet BK, Roth BL. Predicting new molecular targets for known drugs. Nature. 462 (7270), 175-181 (2009).

3. Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry. Nat Biotechnol. 25 (2), 197-206 (2007).