Development of a Fragment-Based <i>in Silico</i> Profiler for Michael Addition Thiol Reactivity

The Adverse Outcome Pathway (AOP) paradigm details the existing knowledge that links the initial interaction between a chemical and a biological system, termed the molecular initiating event (MIE), through a series of intermediate events, to an adverse effect. An important example of a well-defined MIE is the formation of a covalent bond between a biological nucleophile and an electrophilic compound. This particular MIE has been associated with various toxicological end points such as acute aquatic toxicity, skin sensitization, and respiratory sensitization. This study has investigated the calculated parameters that are required to predict the rate of chemical bond formation (reactivity) of a dataset of Michael acceptors. Reactivity of these compounds toward glutathione was predicted using a combination of a calculated activation energy value (<i>E</i>_act, calculated using density functional theory (DFT) calculation at the B3YLP/6-31G+(d) level of theory, and solvent-accessible surface area values (SAS) at the α carbon. To further develop the method, a fragment-based algorithm was developed enabling the reactivity to be predicted for Michael acceptors without the need to perform the time-consuming DFT calculations. Results showed the developed fragment method was successful in predicting the reactivity of the Michael acceptors excluding two sets of chemicals: volatile esters with an extended substituent at the β-carbon and chemicals containing a conjugated benzene ring as part of the polarizing group. Additionally the study also demonstrated the ease with which the approach can be extended to other chemical classes by the calculation of additional fragments and their associated <i>E</i>_act and SAS values. The resulting method is likely to be of use in regulatory toxicology tools where an understanding of covalent bond formation as a potential MIE is important within the AOP paradigm