Antitarget information

In pharmacology, an antitarget (or off-target) is a receptor, enzyme, or other biological target that, when affected by a drug, causes undesirable side-effects. During drug design and development, it is important for pharmaceutical companies to ensure that new drugs do not show significant activity at any of a range of antitargets, most of which are discovered largely by chance.^[1][2]

Among the best-known and most significant antitargets are the hERG channel and the 5-HT_2B receptor, both of which cause long-term problems with heart function that can prove fatal (long QT syndrome and cardiac fibrosis, respectively), in a small but unpredictable proportion of users. Both of these targets were discovered as a result of high levels of distinctive side-effects during the marketing of certain medicines, and, while some older drugs with significant hERG activity are still used with caution, most drugs that have been found to be strong 5-HT_2B agonists were withdrawn from the market, and any new compound will almost always be discontinued from further development if initial screening shows high affinity for these targets.^{[3][4][5][6][7][8]}

Agonism of the 5-HT_2A receptor is an antitarget because 5-HT_2A receptor agonists are associated with hallucinogenic effects.^[9] According to David E. Nichols, "Discussions over the years with many colleagues working in the pharmaceutical industry have informed me that if upon screening a potential new drug is found to have serotonin 5-HT_2A agonist activity, it nearly always signals the end to any further development of that molecule."^[9] There are some exceptions however, for instance efavirenz and lorcaserin, which can activate the 5-HT_2A receptor and cause psychedelic effects at high doses.^[10][11][12]

The growth of the field of chemoproteomics has offered a variety of strategies to identify off-targets on a proteome wide scale.^[13]