Exploring Off-Targets and Off-Systems for Adverse Drug Reactions via Chemical-Protein Interactome — Clozapine-Induced Agranulocytosis as a Case Study

Abstract

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs. Idiosyncratic drug reactions (IDR) generally cannot be identified until after a drug is taken by a large population, but usually result in restricted use or withdrawal. Clozapine provides the most effective treatment for schizophrenia but its use is limited because of a life-threatening IDR, i.e., the agranulocytosis. A high impact clinical study demonstrated the necessity of moving clozapine from 3^rd line to 1^st line drug; therefore, intensive research has aimed at identifying genes responsible for clozapine-induced agranulocytosis (CIA). Olanzapine, an analog of clozapine, has much lower incidence of agranulocytosis. Based on this phenomenon, we proposed an in silico methodology termed as antithesis chemical-protein interactome (CPI), which mimics the differences in the drug-protein interactions of the two drugs across a panel of human proteins. e.g., HSPA1A was identified to be targeted by clozapine not olanzapine. Furthermore, the gene expression of the HSPA1A-related gene system was also found up-regulated after clozapine treatment. This approach can examine the system's perturbation in terms of both the off-target and the off-system's interaction with the drug, providing theoretical basis for decoding the adverse drug reactions or the new uses for old drugs.