The identification of genetic factors that influence drug responses often focuses on genes
whose variants are predicted to alter pharmacokinetic and/or pharmacodynamic parameters—leading
to an increased risk of drug toxicity or therapeutic failure. In this study, we selected 48 genes identified
as “Very Important Pharmacogenes (VIPs)” by the PharmGKB database, and developed a fivefeature
Structural Disturbance Score (SDS) for their amino acid variants. “SDS Pharmacogenes” is a
score that categorizes distinguishable characteristic profiles that annotate VIP variants as functional
rather than neutral mutations. Unlike most existing conservation-based measures, SDS Pharmacogenes
can be used to evaluate unknown variants of currently 45/48 VIPs and predict the degree to which
each one will have strong impacts towards pharmacogenomics, potentially aiding optimization of drug therapy. SDS
Pharmacogenes is built upon a systematic screening for structural disturbance of amino acid mutations within the 45/48
VIPs in the context of their 3-dimensional (3D) protein structures. Our variant evaluation pipeline focuses on the changes
in inter-residue bonding, protein stability, protein flexibility, drug binding capability, protein-protein interactions, and
amino acid dissimilarity, in addition to the localization of the variants and the amino acid secondary structure preference.
While expertise in 3D-protein analysis is beneficial, our implementation does not require that an individual with experience
in protein structures be engaged in the personalized genome evaluation, nor expect the users must have bioinformatic
backgrounds. In addition, the analysis pipeline is systematic and scalable, thus expected to keep pace with the rapid accumulation
of pharmacogenomic data. The SDS Pharmacogenes web application is publicly available at http://sdsp.
Keywords: 3D protein structures, amino acid mutations, PharmGKB, SDS pharmacogenes, structural analysis, structural disruption
index (SDI), structural disturbance score (SDS), very important pharmacogenes (VIP).
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