Abstract
Animal testing remains a contentious ethical issue in predictive toxicology. Thus, a fast, versatile, low-cost quantum chemical model is presented for predicting the risk of Ames mutagenicity in a series of 1,4 Michael acceptor type compounds. This framework eliminates the need for transition state calculations, and uses an intermediate structure to probe the reactivity of aza-Michael acceptors. This model can be used in a variety of settings e.g., the design of targeted covalent inhibitors and polyketide biosyntheses.
Highlights
Animal testing remains a contentious ethical issue in predictive toxicology
This framework eliminates the need for transition state calculations, and uses an intermediate structure to probe the reactivity of aza-Michael acceptors
A positive Ames test result on novel drug candidates can be a significant roadblock in their development; it is indicative of a hazardous chemotype and can often halt clinical trials on potential therapeutics.[7]
Summary
A fast, versatile, low-cost quantum chemical model is presented for predicting the risk of Ames mutagenicity in a series of 1,4 Michael acceptor type compounds. In 2019, we published a model that utilised DFT TSM to predict the Ames test results of 30 1,4 Michael acceptors, with activation free energy and LUMO energies showing significant correlation with mutagenic risk.[13] Our results showed that a higher level of theory in the molecular geometry optimisation procedure had a direct effect on the quality of the reactivity predictions made on the original dataset of 19 MAs.[14] Despite significant predictive potential shown by the model, TSM can be costly, exhaustively time consuming and challenging for the non-expert.
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