A comprehensive map of molecular drug targets

• Published in: Nature reviews. Drug discovery Vol. 16; no. 1; pp. 19 - 34
• Main Authors: Santos, Rita, Ursu, Oleg, Gaulton, Anna, Bento, A. Patrícia, Donadi, Ramesh S., Bologa, Cristian G., Karlsson, Anneli, Al-Lazikani, Bissan, Hersey, Anne, Oprea, Tudor I., Overington, John P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2017; Nature Publishing Group
• Subjects: 631/154/109; 631/154/2426; 631/61; 692/308/153; 692/700/565/1436; analysis; Biomedicine; Biotechnology; Cancer Research; Databases, Pharmaceutical; Drug Approval; Drug Delivery Systems - trends; Drug Discovery - trends; Drug Prescriptions - statistics & numerical data; Genetic Variation; Genome, Human; Humans; Innovations; Medicinal Chemistry; Molecular Medicine; Molecular targeted therapy; Pharmaceutical industry; Pharmacogenetics - trends; Pharmacological research; Pharmacology/Toxicology; Product development; United States; United States Food and Drug Administration
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/nrd.2016.230

Key Points
The definition of a drug target is crucial to the success of mechanism-based drug discovery. It is also increasingly important for efforts to link drug response to genetic variation, understand stratified clinical efficacy and safety, rationalize the differences between drugs in the same therapeutic class and predict drug utility in patient subgroups.
In this article, we synthesized and built on our previous approaches and systematically recompiled and comprehensively annotated the current list of drugs approved by the US FDA. We assigned to each drug their respective efficacy target or target set from the prescribing information and/or the scientific literature.
We curated a total of 893 human and pathogen-derived biomolecules through which 1,578 FDA-approved drugs act. These include 667 human-genome-derived proteins targeted by drugs for human disease.
We emphasize that even with a well-defined concept of efficacy there are challenges in making a clean unambiguous assignment in many cases, especially regarding how to treat protein complexes or drugs that bind to a number of closely related gene products.
We also mapped each drug (and thereby target) to the WHO Anatomical Therapeutic Chemical Classification System code as a way of obtaining a standard therapeutic indication for them.
With this mapping, we explored the footprint of target classes across disease areas, investigated the success of privileged target families and compiled a list of drug target orthologues for standard model organisms to develop a foundation for the deeper understanding of species differences, cross-species drug repositioning and applicability of animal models.
The success of mechanism-based drug discovery depends on the definition of the drug target, but targets are often poorly defined in the literature. Here, Overington and colleagues present a comprehensive map of the molecular targets of approved drugs, and explore aspects including the footprint of target classes across disease areas, the success of privileged target families and drug target orthologues across standard model organisms.
The success of mechanism-based drug discovery depends on the definition of the drug target. This definition becomes even more important as we try to link drug response to genetic variation, understand stratified clinical efficacy and safety, rationalize the differences between drugs in the same therapeutic class and predict drug utility in patient subgroups. However, drug targets are often poorly defined in the literature, both for launched drugs and for potential therapeutic agents in discovery and development. Here, we present an updated comprehensive map of molecular targets of approved drugs. We curate a total of 893 human and pathogen-derived biomolecules through which 1,578 US FDA-approved drugs act. These biomolecules include 667 human-genome-derived proteins targeted by drugs for human disease. Analysis of these drug targets indicates the continued dominance of privileged target families across disease areas, but also the growth of novel first-in-class mechanisms, particularly in oncology. We explore the relationships between bioactivity class and clinical success, as well as the presence of orthologues between human and animal models and between pathogen and human genomes. Through the collaboration of three independent teams, we highlight some of the ongoing challenges in accurately defining the targets of molecular therapeutics and present conventions for deconvoluting the complexities of molecular pharmacology and drug efficacy.