Computational journey to unveil organophosphorothioate pesticides’ metabolism: A focus on chlorpyrifos and CYP2C19 mutational landscape

Organophosphorothioates (OPT) are pesticides impacting human, animal and environmental health. They enter the environment worldwide, primarily due to their application as insecticides. OPTs are mainly neurotoxic upon bioactivation and inhibition of brain and serum acetylcholinesterase (AChE). Although OPTs are meant to target insects, they are potentially toxic to many other species (including humans), posing risks to non-target organisms and ecosystems. Certain cytochromes P450 (CYP) promote OPTs bioactivation, forming the corresponding oxon metabolites, while others catalyse their detoxification. Understanding the molecular basis of such a bivalent fate may help to clarify the toxicity of OPTs in living organisms, with far-reaching consequences to understand their impact on living organisms and improve risk assessment, to cite but a few. However, although crucial, the underpinning mechanisms still lay unclear. Here, a validated computational pipeline revealed the molecular reasons underlying the differential metabolism of chlorpyrifos in humans by CYP2C19, a primal route of detoxification, and its bioactivation by CYP2B6. The analysis drew the diverse occupancy of the CYP pocket and orientation to the heme group as a convincing evidence-based explanation for the opposite transformation. Moreover, this study explored the impact of CYP2C19 mutational landscape giving a blueprint to unveil the molecular basis of OPTs metabolism and toxicological implications from an inter-individual perspective. Taken together, the outcome described for the first time to the best of our knowledge a structural rationale for the bioactivation/detoxification of OPTs improving the current understanding of their toxicity from a molecular standpoint.