A Structure-Based Approach for Mapping Adverse Drug Reactions to the Perturbation of Underlying Biological Pathways

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 examined a dataset of 506 ADRs, 730 drugs, and 830 human protein targets. Our method yielded 185 ADR-pathway associations of which 45 were selected to undergo a manual literature review. We found 32 associations to be supported by the scientific literature.

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

“…multiple targets implicated for one disease state [342]) and the robust or compensatory behaviour of biological systems [348] suggest that designing selectively promiscuous compounds may offer better therapeutic outcomes [349]. Likewise, prediction of compound polypharmacology has the potential to identify possible adverse effects [350,351] which are implicated in about 30% of drug failures.…”

Predicting Drug Safety: Next Generation Solutions

“…The consequences of not developing such a system have been evident by the cost of drug safety issues to the health care system and the increasing costs of developing new drugs which in great part reflect the difficulty in establishing and proving adequate risk/benefit ratios in the expected patient populations. New 'omics technologies coupled with bioinformaticssystems biology approaches including genome wide association studies (GWAS) and biological pathway analysis are adding new insights into possible mechanisms, identification of susceptible individuals, and points of potential intervention [2,3].…”

“…Newer efforts focused on next generation sequencing in the study of disease as well as predicting human drug responses both positive and negative are emerging. We anticipate an extensive body of knowledge to develop, which will enable a predictive process that takes the theoretical drug directly to the bedside and back during the design phase [2,3,[8][9][10][11].…”

“…This approach as applied in a global sense has great potential merit, even though the described network is limited to the applicability domain of the drugs and events within the training sets of the model. In another systems approach, Wallach et al [2] designed a computational framework to pair drugs and associated ADRs by using in silico protein docking with relevant protein targets and biological pathways to define ADR-pathway associations. This resulted in 32 probable ADR pathways.…”

Maestro 9.4 as a Tool in the Structure Based Screening of Glycoalkaloids and Related Compounds, Targeting Aldose Reductase

“…Understanding the interaction of drugs with the biological processes ensures safe medication. Management of diabetes is thus still a challenge to the medical system (Angadi et al, 2013;Williams and Pickup, 1991;Senthilraja et al, 2013;Wallach et al, 2010). Recently, the growth in the sales of anti-diabetic molecules has increased by lifestyle ailments in India.…”