Chemically similar drugs often bind biologically diverse targets, yet most drugs are presumed selective at therapeutic concentrations. To investigate this assumption, we computationally compared 3,665 FDA-approved and investigational drugs against a panel of over 100,000 ligands organized into hundreds of sets according to the targets they modulate. More than 25 novel off-target drug activities were predicted and confirmed in pharmacological assays, five below 100 nM. The chemical similarity approach used here is systematic and comprehensive, and it is being used to predict drug and drug candidate toxicities, and to find new therapeutic indications for drugs. It is also used more generally to predict the biological target of any molecule based on its topology alone.
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 KL, Edwards DD, Shoichet BK, Roth BL. Predicting drug off-targets. Nature 462, 175-81 (2009).
Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry. Nature Biotech 25, 197-206 (2007).
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