Development of a fragment-based in silico profiler for SN2 thiol reactivity and its application in predicting toxicity of chemicals towards Tetrahymena pyriformis
Ebbrell, DJ, Madden, JC, M Cronin, Schultz, T, Enoch, SJ · Computational Toxicology · 2019
This study outlines the development of a fragment-based in silico profiler for SN2 thiol reactivity. The chemical space of the profiler related to a dataset of glutathione reactivity data for SN2 chemicals acti- vated by the presence of an electron-withdrawing carbonyl group. The approach is in keeping with a recently developed fragment-based in silico profiler for Michael addition thiol reactivity and involved developing a database of structural alert-type fragments with associated activation energy values (ΔEReact-TS). These energy values were calculated using density functional theory with a B3YLP functional coupled to a 6-31G + (d) basis set. The results showed the fragment-based in silico profiler for SN2 reactivity was able to successfully predict glutathione reactivity and toxicity to Tetrahymena pyriformis. Overall, the results of this study extend the previous fragmentbased profiler development to the SN2 domain and further validate the approach. The study also highlights the ability of the fragment-based in silico profilers to predict toxicological potency where the formation of a covalent bond is the key molecular initiating event.