In silico methods are invaluable tools to researchers seeking to understand and predict metabolic processes within PBPK models. Even though these methods have been successfully utilized to predict and quantify metabolic processes, there are many challenges involved. Stereochemical processes are a particular challenge since they require computational methods that can elucidate 3D structures and their inherent conformational dependence within a biological context. Developed methods to estimate stereoselective metabolic hydrolysis in mammals are presented to aid PBPK modelers in determining qualitative as well as quantitative relationships among the chiral pyrethroid pesticides. We illustrate a case example of rat serum carboxylesterase (rsCE)-mediated hydrolysis of 27 pyrethroid stereisomers elucidated through a proposed three-step in silico workflow. The methodology involves (ⅰ) a pharmacophore structural qualifier/filter to determine whether or not a particular stereoisomer is indeed a viable substrate, and (ⅱ) a mechanism-specific quantitative structure activity relationship (QSAR) to predict metabolic rate constants. Our strategy extends the utility of pharmacophore filters in the reduction of misclassification of mechanistically competent substrates, while strengthening the utility of QSAR models within PK/PD model development.
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