13 research outputs found
Exploring Off-Targets and Off-Systems for Adverse Drug Reactions via Chemical-Protein Interactome — Clozapine-Induced Agranulocytosis as a Case Study
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
Association of disease-predisposition polymorphisms of the melatonin receptors and sunshine duration in the global human populations
Quinone Reductase 2 Is a Catechol Quinone Reductase*S⃞
The functions of quinone reductase 2 have eluded researchers for decades
even though a genetic polymorphism is associated with various neurological
disorders. Employing enzymatic studies using adrenochrome as a substrate, we
show that quinone reductase 2 is specific for the reduction of adrenochrome,
whereas quinone reductase 1 shows no activity. We also solved the crystal
structure of quinone reductase 2 in complexes with dopamine and adrenochrome,
two compounds that are structurally related to catecholamine quinones.
Detailed structural analyses delineate the mechanism of quinone reductase 2
specificity toward catechol quinones in comparison with quinone reductase 1; a
side-chain rotational difference between quinone reductase 1 and quinone
reductase 2 of a single residue, phenylalanine 106, determines the specificity
of enzymatic activities. These results infer functional differences between
two homologous enzymes and indicate that quinone reductase 2 could play
important roles in the regulation of catecholamine oxidation processes that
may be involved in the etiology of Parkinson disease
Association of HLA-B and HLA-DRB1 polymorphisms with antithyroid drug-induced agranulocytosis in a Han population from northern China
Quinone oxidoreductases in protection against myelogenous hyperplasia and benzene toxicity
Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population
Personalised Therapeutic