Systematic 3D Screening of Amino Acid Mutations in Pharmacogenes

Author(s): Thanawadee Preeprem, Greg Gibson.

Journal Name: Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics)

Volume 12 , Issue 4 , 2014

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Abstract:

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. cig.biology.gatech.edu.

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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Article Details

VOLUME: 12
ISSUE: 4
Year: 2014
Page: [209 - 226]
Pages: 18
DOI: 10.2174/1875692113666150408222109

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