Human CYP2C9 metabolism of organophosphorus pesticides and nerve agent surrogates

Of the Cytochrome P450 enzymes, the CYP2C9 variant is very important and is the cytochrome P450 (CYP) involved in the metabolism of several human drugs where it acts as a natural bioscavenger. Previously, CYP2C9 was demonstrated to remove sulfur from different organophosphorus (OP) pesticides, such as dimethoate, diazinon and parathion. In this study, we have tested the ability of CYP2C9 to degrade other OP compounds. We investigated the metabolism of OP compounds by CYP2C9 using LC-MS/MS approaches as well as the time-dependent inhibition of CYP2C9 by OP compounds using the previously developed pFluor50 fluorogenic assay. We found that CYP2C9 metabolizes thions (P=S) preferentially over oxons (P=O) and there were many OP compounds that inhibited CYP2C9 activity in a time-dependent manner. Additionally, we performed molecular docking based on the Protein Data Bank (PDB)crystal structure (1OG5) of the CYP2C9 receptor in order to gain atomistic insight from the in vitro experimental results. We observed a positive though moderate correlation between the calculated binding energy and the CYP2C9 metabolism of various OP compounds (R = 0.61) as well as the time-dependent changes in inhibition of OPs with binding energy (R = 0.59). Although the R values were modest,59). These in vitro data combined with analysis of additional OP derivatives could be used to develop artificial intelligence (AI)machine learning models to predict the metabolism of specific OP compounds by CYP2C9. This type of approach could be particularly relevant for the prediction of the metabolism of current and emerging chemical warfare agents.