a structure-based approach for mapping adverse drug reactions to the perturbation of underlying biological pathways基于结构的方法映射药品不良反应的潜在生物学途径的扰动.pdfVIP

A Structure-Based Approach for Mapping Adverse Drug Reactions to the Perturbation of Underlying Biological Pathways 1,3 1 1,2,3 Izhar Wallach *, Navdeep Jaitly , Ryan Lilien * 1 Department of Computer Science, University of Toronto, Toronto, Ontario, Canada, 2 Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada, 3 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada Abstract Adverse drug reactions (ADR), also known as side-effects, are complex undesired physiologic phenomena observed secondary to the administration of pharmaceuticals. Several phenomena underlie the emergence of each ADR; however, a dominant factor is the drug’s ability to modulate one or more biological pathways. Understanding the biological processes behind the occurrence of ADRs would lead to the development of safer and more effective drugs. At present, no method exists to discover these ADR-pathway associations. In this paper we introduce a computational framework for identifying a subset of these associations based on the assumption that drugs capable of modulating the same pathway may induce similar ADRs. Our model exploits multiple information resources. First, we utilize a publicly available dataset pairing drugs with their observed ADRs. Second, we identify putative protein targets for each drug using the protein structure database and in-silico virtual docking. Third, we label each protein target with its known involvement in one or more biological pathways. Finally, the relationships among these information sources are mined using multiple stages of logistic-regression while controlling for over-fitting and multiple-hypothesis testing. As proof-of-concept, we exam