Molecular Docking Studies of the Action Mode of Formamidine Insecticides on Octopamine Receptors of Cockroach, House Fly, and Mosquito
Steve Darole Kamguia, Eric N. Njabon, Issofa Patouossa, Alphonse Emadak
Computational and Structural Biotechnology Reports
Formamidine insecticides selectively disrupt invertebrate neurotransmission by targeting octopamine receptors (OARs), yet the atomistic mechanisms governing their binding remain poorly characterized. To address this gap, an integrated in silico strategy combining density functional theory, molecular docking, statistical analysis, and molecular dynamics simulations was applied—a multilevel approach not previously used for this ligand–receptor system across multiple insect species. Eight formamidine derivatives were investigated against AlphaFold-predicted OAR structures from Periplaneta americana , Musca domestica , and Culex quinquefasciatus , validated by redocking and structural alignment with the human β 2 -adrenergic receptor (Protein Data Bank: 2RH1). Results demonstrate that all formamidines and the endogenous ligand, octopamine, bind strongly, with binding free energies ranging from −5.2 to −8.5 kcal·mol −1 . Amitraz consistently showed the strongest affinity across all species ( P < 0.001), driven by extensive π–alkyl, π–π, and hydrophobic interactions. A moderate inverse correlation between ligand molecular mass and binding free energy ( R = −0.60 to −0.74) indicates that larger ligands achieve stronger hydrophobic complementarity within the receptor cavity, with this effect attenuated by ligand reactivity, as demonstrated by density functional theory calculations. Molecular dynamics simulations and molecular mechanics generalized Born surface area calculations confirmed superior dynamic stability of the amitraz complex (Δ G bind = −17.37 ± 5.79 kcal·mol −1 ) relative to octopamine (−10.43 ± 4.50 kcal·mol −1 ), with lower root-mean-square deviation values and maintained transmembrane integrity throughout the 100-ns trajectory. These findings establish molecular reactivity, aromaticity, hydrophobicity, and molecular size as key determinants of OAR binding affinity and provide a molecular-level foundation for the rational design of selective insecticides targeting octopaminergic pathways in insect pests.