For the past decade, the number of molecular targets for approved drugs has been debated. Here, we reconcile apparently contradictory previous reports into a comprehensive survey, and propose a consensus number of current drug targets for all classes of approved therapeutic drugs. One striking feature is the relatively constant historical rate of target innovation (the rate at which drugs against new targets are launched); however, the rate of developing drugs against new families is significantly lower. The recent approval of drugs that target protein kinases highlights two additional trends: an emerging realization of the importance of polypharmacology, and also the power of a gene-family-led approach in generating novel and important therapies.
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We thank I. Carruthers, R. Cox, S. Rehman and J. Stevenson for assistance with data curation and analysis.
John Overington and Bissan Al-Lazikani are employees of Inpharmatica Ltd. Andrew Hopkins is an employee of Pfizer.
- Cytochrome P450 3A4
This enzyme is arguably the most important enzyme for drug metabolism; it metabolizes more than 50% of marketed drugs, and is frequently involved in drug–drug interactions.
- New molecular entity
A drug that contains an active ingredient that has not been previously approved by the US FDA.
The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.
Here we use polypharmacology to mean the binding of a drug to multiple target proteins, with clinical effects being mediated through the modulation of the set of protein targets.
- Privileged druggable domains
A functional domain of a protein for which a significant fraction of family members have been successfully targeted by drugs. Rhodopsin-like GPCRs, certain ion-channel domains and nuclear receptor ligand-binding domains are clear historical examples of druggable domains.
A drug that requires conversion to a more active pharma-cological form following dosing. This conversion is often performed by endogenous enzymes. Prodrugs are generally used to overcome problems with stability, toxicity or often limited oral bioavailability of the pharmacologically active form.
Poor absorption or permeation of a compound is more likely when there are >5 hydrogen bond donors, the molecular mass is >500, cLogP is >5, and the sum of nitrogen and oxygen atoms in a molecule is greater than 10. Many drugs, however, are exceptions to the rule-of-five, and often these are substrates for biological transporters.
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Overington, J., Al-Lazikani, B. & Hopkins, A. How many drug targets are there?. Nat Rev Drug Discov 5, 993–996 (2006). https://doi.org/10.1038/nrd2199
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