Drug toxicity is often caused by electrophilic reactive molecules that covalently bind to proteins. Consequently, the quantitative strength of a molecule’s reactivity with glutathione (GSH) is a frequently used indicator of its toxicity. GSH scavenges reactive molecules in the body, so molecules that react with it are likely to covalently link with proteins. Moreover, GSH conjugates to specific atoms in reactive molecules, their sites of reactivity. The value of knowing a molecule’s sites of reactivity is unexplored in the literature. This study tests the value of site of reactivity data—which identifies the atoms within 1075 reactive molecules that conjugate to GSH—in building models to predict molecular reactivity with glutathione. An algorithm originally written to model sites of P450 metabolism (called XenoSite) finds clear patterns in molecular structure that identify sites of reactivity within reactive molecules with 91.8% accuracy and separate reactive and unreactive molecules with 83.2% accuracy. Moreover, the model’s output strongly correlates with quantitative GSH reactivity data in chemically diverse, external datasets. Site of reactivity data is nearly unstudied in the literature, but contains a strong signal for reactivity that can be utilized to more accurately predict molecule reactivity and, eventually, toxicity.

Site of reactivity models predict molecular reactivity of diverse chemicals

249th National Meeting (2015)

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