Genomic analysis of human polymorphisms affecting drug-protein interactions

2017.

Pich i Rosello O., Vlasova A., Shichkova P., Markov Yuri, Vlasov P., Kondrashov F. A.

Human genetic variability is thought to account for a substantial fraction of individual biochemical characteristics — in biomedical sense, of individual drug response. However, only a handful of human genetic variants have been linked to medication outcomes. Here, we combine data on drug-protein interactions and human genome sequences to assess the impact of human variation on their binding affinity. Using data from the complexes of FDA-drugs and drug-like compounds, we predict SNPs substantially affecting the protein-ligand binding affinities. We estimate that an average individual carries ~6 SNPs affecting ~5 different FDA-approved drugs from among all of the approved compounds. SNPs affecting drug-protein binding affinity have low frequency in the population indicating that the genetic component for many ADEs may be highly personalized with each individual carrying a unique set of relevant SNPs. The reduction of ADEs, therefore, may primarily rely on the application of computational genome analysis in the clinic rather than the experimental study of common SNPs.

Keywords: drug design