GPCRs As Drug Targets: Nowhere Near Played Out

Here's a paper that asks whether GPCRs are still a source of new targets. As you might guess, the answer is "Yes, indeed". (Here's a background post on this area from a few years ago, and here's my most recent look at the area). It's been a famously productive field, but the distribution is pretty skewed: From a total of 1479 underlying targets for the action of 1663 drugs, 109 (7%) were GPCRs or GPCR related (e.g., receptor-activity modifying proteins or RAMPs). This immediately reveals an issue: 26% of drugs target GPCRs, but they account for only 7% of the underlying targets. The results are heavily skewed by certain receptors that have far more than their “fair share” of drugs. The most commonly targeted receptors are as follows: histamine H1 (77 occurrences), α1A adrenergic (73), muscarinic M1 (72), dopamine D2 (62), muscarinic M2 (60), 5HT2a (59), α2A adrenergic (56), and muscarinic M3 (55)—notably, these are all aminergic GPCRs. Even the calculation that the available drugs exert their effects via 109 GPCR or GPCR-related targets is almost certainly an overestimate since it includes a fair proportion where there are only a very small number of active agents, and they all have a pharmacological action that is “unknown”; in truth, we have probably yet to discover an agent with a compelling activity at the target in question, let alone one with exactly the right pharmacology and appropriately tuned pharmacokinetics (PK), pharmacodynamics (PD), and selectivit...
Source: In the Pipeline - Category: Chemists Tags: Drug Assays Source Type: blogs