Physical Sciences and Mathematics Commons^™

Modeling The Bioactivation And Subsequent Reactivity Of Drugs, Tyler Brian Hughes

Arts & Sciences Electronic Theses and Dissertations

Metabolism can convert drugs to harmful reactive metabolites that conjugate to DNA and off-target proteins. Reactive metabolites are a significant driver of both drug candidate attrition and withdrawal from the market of already approved drugs. Unfortunately, reactive metabolites are difficult to study in vivo, because they are transitory and generally do not circulate. Instead, this work computationally models both metabolism and reactivity. Using deep learning, predictive models were developed for the metabolic formation of quinones and epoxides, which together account for about half of known reactive metabolites. Additionally, an accurate model of DNA and protein reactivity was constructed, which predicts …