Identifying Genetic Contributions to Adverse Drug Reactions

确定基因对药物不良反应的影响

Identifying Genetic Contributions to Adverse Drug Reactions Project Summary Bioinformatics tools will be created that facilitate searching the genome for variants that can elucidate previously unexplained adverse drug reactions (ADRs). Known protein targets for pharmaceuticals represent only a few percent of the genome and this is a missed opportunity in drug design and in finding genetic explanations for ADRs. We are seeking to create new bioinformatics tools for identifying the off-target binding sites of pharmaceuticals and their metabolites. Our goal is to build tools that help identify the underlying genetic causes of rare and unexplained ADRs so these effects can be avoided. Our initial focus will be on very large existing data sets on genetic variation and on ADRs that are currently not linked to identify possible new connections between the datasets. The first specific aim is to create a docking server using the best available protein structures so that variants of any protein can be used in docking studies and be examined as a source of possible side effects expanding into the dark genome. The second specific aim is to create online tools that identify specific ADRs and produce the three-dimensional structures of drugs and drug metabolites prepared for docking studies and create fast screening tools. Together these tools can be used by researchers to prioritize drug protein interactions for further in silico or in vitro studies. These tools will facilitate rapid testing of hypotheses about molecular causes of harmful drug side effects in both available drugs and drugs being designed today, a critical step toward eliminating ADRs and designing more effective drugs.