Identifying the Molecular Targets of Therapeutic Drugs

Drugs exert their therapeutic effects by binding and regulating the activity of a particular protein or nucleic acid target. Efforts to quantify and describe the number of drugged and druggable proteins that are encoded by the human genome have resulted in different estimates that range in the low hundreds. In these findings, G protein-coupled receptors (GPCRs) represent the highest number of drug targets, followed by enzymes. Imming et. al. (2006) estimated a number of 218 molecular targets for approved drugs, while Zheng et. al. (2006) identified 268 successful targets in the current version of the Therapeutics Targets Database. We set out to identify the current number of molecular targets of therapeutic drugs a decade since these observations, and to assess the proportion whose effects were mediated principally through GPCR.

Using the British National Formulary as a data source, the 1395 drugs in the BNF were analysed by chapter. The primary targets were divided into human, non-specific, and pathogen, while drugs with unknown targets and those delivered as drug mixtures were also enumerated. The major pharmacological targets were divided into seven focus areas: GPCRs, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters, and enzymes, based on the compilation used in The Concise Guide to PHARMACOLOGY (Alexander et al., 2013). For each drug, the targets were identified according to class (receptor, enzyme, transporter, pathogen, non-specific, channel), subclass, family, and subtype. Primary clinical targets were assigned to each drug using the Guide to PHARMACOLOGY database and literature sourcing, and thereafter analysed using Microsoft Excel.

In summary, 163 effect-mediating drug targets in the human genome were identified, where GPCRs represent the highest number of targets of drugs listed in the BNF at 33%, followed by enzymes at 22%, and ion channels which comprise 6% of all drug targets. The smaller number of targets compared to previous analysis may reflect geographic differences in drug usage, drug withdrawals or differences in the assignment of molecular targets. As with the previous analyses, GPCR continue to represent the major group of targets exploited in man.

Alexander, S., Benson, H., Faccenda, E., & Pawson, A, et. al. (2013). The Concise Guide to PHARMACOLOGY 2013/14. British Journal of Pharmacology, 170, 1449-1867

Imming, P., Sinning, C., & Meyer, A. (2006). Drugs, their targets and the nature and number of drug targets. Nature Reviews Drug Discovery, 821-834.

Zheng, C. (2006). Therapeutic Targets: Progress of Their Exploration and Investigation of Their Characteristics. Pharmacological Reviews, 58, 259-279.