Abstract
The discovery of a drug requires over a decade of intensive research and financial investments - and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch resource, which incorporates 250,000 bioactive molecules, and studied their enzymatic metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug-drug and drug-metabolite pairs. We validated the application, scope, and performance of NICEdrug.ch over similar methods in the field on golden standard datasets describing drugs and metabolites sharing reactivity, drug toxicities, and drug targets. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1300 candidate drugs and food molecules to target COVID-19 and explains their inhibitory mechanism for further experimental screening. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.
Highlights
To assure effective therapies for previously untreated illness, emerging diseases, and personalized medicine, new small molecules are needed
10.4% of identified reactive sites correspond to the p450 class of enzymes, which are responsible for breaking down compounds in the human body by introducing reactive groups on those compounds, known as phase I of drug metabolism (Figure 1—figure supplement 2A)
The analysis involved over 250,000 small molecules, and curation and computation of bio- and physico-chemical drug properties that we assembled in an open-source drug database NICEdrug.ch that can generate detailed drug metabolic reports and can be accessed and used by researchers, clinicians, and industry partners
Summary
To assure effective therapies for previously untreated illness, emerging diseases, and personalized medicine, new small molecules are needed. The process to develop new drugs is complex, costly, and time consuming. This is especially problematic considering that about 90% of drug candidates in clinical trials are discarded due to unexpected toxicity or other secondary effects. This inefficiency threatens our health care system and economy (Wong et al, 2019). The biochemical space of small molecules and possible targets in the cell is huge, which limits the possible experimental testing.
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