In silico investigation of functional nsSNPs – an approach to rational drug design
IMDEA Food Institute, Madrid, Spain
Abstract: Nonsynonymous single-nucleotide polymorphisms (nsSNPs) of genes are coding variants that introduce amino acid changes to proteins. Because nsSNPs have diverse effects on protein structure and function, these variants can have a large impact on human health. Likewise, polymorphisms in genes encoding drug targets directly affect target protein function, drug–target interaction, or both to produce profound effects on drug response. Pharmacogenomics provides insight into how polymorphisms can affect drug responses that vary from potentially fatal adverse drug reactions to equally severe lack of therapeutic efficacy. This review focuses on the effects of deleterious nsSNPs at both functional and structural protein level, as well as on protein–protein interactions. It also explains current methods by which to predict the functional impact of nsSNPs based on physicochemical amino acid properties, sequence information, and structural attributes. Additionally, the review details the recent advances in the field of in silico pharmacogenomics, which provide insight into disease phenotypes and individual susceptibility to disease. In the near future, this information will be used to predict the most appropriate treatment and individualized drug therapy. Finally, this article provides an overview of in silico approaches for the assessment and development of safe and efficient tailored drugs.
Keywords: pharmacogenomics, nonsynonymous single-nucleotide polymorphisms, drug responses, drug-target protein, personalized medicine