STRUCTURE-BASED VIRTUAL SCREENING AND MOLECULAR DYNAMICS APPROACHES TO TARGET CYP9E2 FOR COMBATING INSECTICIDE RESISTANCE Authors: Khazina Begum, Muhammad Haseeb, Raisa Bano, Surrya Khanam Journal: Journal of Animal and Plant Sciences (JAPS) ISSN: 1018-7081 (Print), 2309-8694 (Online) Volume: 37 Issue: 1 Year: 2027 DOI: https://doi.org/10.36899/JAPS.2027.1.0002 URL: https://doi.org/https://doi.org/10.36899/JAPS.2027.1.0002 Publisher: Pakistan Agricultural Scientists Forum Abstract:

Insecticide resistance in pests such as bed bugs, mosquitoes, and cockroaches poses a major challenge in urban pest management and public health by reducing the effectiveness of insecticides and increasing control costs. One of the primary mechanisms underlying insecticide resistance is cytochrome P450-mediated metabolic detoxification. The present study focuses on targeting CYP9E2, a member of the Cytochrome P450 monooxygenase enzymes involved in xenobiotic metabolism and detoxification, to identify potential inhibitors that could overcome insecticide resistance. Structure-based virtual screening, molecular docking, and molecular dynamics simulations were employed to identify potent CYP9E2 inhibitors. A three-dimensional model of CYP9E2 was constructed, and the binding interactions between the selected compounds and key active-site residues were comprehensively analysed. Additionally, the ADMET and agrochemical-likeness (ag-like) properties of the shortlisted inhibitors were evaluated to assess their potential as agrochemical agents. The results indicate that two compounds, ZINC09060935(ethyl3-{[(2-hydroxyethyl) (methyl)carbamoyl]amino}-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]pyridine-2-carboxylateand) and ZINC32091018 (1-(3-Chlorophenyl)-6,7-dimethoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)(morpholino) methanone), are promising candidates with potential inhibitory activity against CYP9E2. The ADMET and ag-like predictions confirmed agrochemical-likeness criteria of the lead compounds, indicating their potential as CYP9E2 inhibitors. However, further in vitro and in vivo experiments can validate the effectiveness, safety, and applicability of these newly developed resistance-modulating agents for pest management.

Keywords: small-molecule inhibitor, MD simulation, insecticide resistance, CYP9E2, cytochrome P450.