Understanding the mechanisms underlying drug therapeutic action and toxicity is crucial for the prevention and management of drug adverse reactions, and paves the way for a more efficient and rational drug design. The characterization of drug targets, drug metabolism proteins, and proteins associated to side effects according to their expression patterns, their tolerance to genomic variation and their role in cellular networks, is a necessary step in this direction. In this contribution, we hypothesize that different classes of proteins involved in the therapeutic effect of drugs and in their adverse effects have distinctive transcriptomics, genomics and network features. We explored the properties of these proteins within global and organ-specific interactomes, using multi-scale network features, evaluated their gene expression profiles in different organs and tissues, and assessed their tolerance to loss-of-function variants leveraging data from 60K subjects. We found that drug targets that mediate side effects are more central in cellular networks, more intolerant to loss-of-function variation, and show a wider breadth of tissue expression than targets not mediating side effects. In contrast, drug metabolizing enzymes and transporters are less central in the interactome, more tolerant to deleterious variants, and are more constrained in their tissue expression pattern. Our findings highlight distinctive features of proteins related to drug action, which could be applied to prioritize drugs with fewer probabilities of causing side effects.

We received support from ISCIII-FEDER (PI13/00082, CP10/00524, and CPII16/00026), IMI-JU under grant agreements no. 116030 (TransQST) and no. 777365 (eTRANSAFE) resources of which are composed of financial contribution from the EU-FP7 (FP7/2007-2013) and EFPIA companies in kind contribution, and the EU H2020 Program 2014–2020 under grant agreements no. 634143 (MedBioinformatics) and no. 676559 (Elixir-Excelerate). The Research Programme on Biomedical Informatics (GRIB) is a member of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and was supported by grant PT13/0001/0023, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER. The DCEXS is a “Unidad de Excelencia María de Maeztu”, funded by the MINECO (ref: MDM-2014-0370). AG-P was supported by a Ramón y Cajal contract (RYC-2013-14554). BO and JA-P were supported by MINECO grant BIO2014-57518-R.