Structural and Biological Evidence for Acetylcholinesterase-Targeted Insecticidal Activity in Musca domestica: A 4.5 Å Distance Correlation From Novel Benzenesulfonamide Derivatives
Abstract
House fly (Musca domestica) control faces mounting resistance to conventional insecticides, driving interest in novel chemistries targeting acetylcholinesterase (AChE). We examined eight benzenesulfonamide derivatives originally developed as carbonic anhydrase inhibitors to explore their potential as AChE-targeting insecticides and to identify structural determinants of biological activity. Using a high-quality homology model of M. domestica AChE, we performed blind docking, refined docking to the peripheral anionic site, 100 ns molecular dynamics simulations, and molecular mechanics-poisson-boltzmann surface area (MM-PBSA) binding energy calculations. All eight compounds showed favorable binding energies (-8.5 to -10.2 kcal/mol) and stable trajectories, yet bioassays revealed a stark divide: five compounds (16b, 16c, 16d, 19b, and 19f) produced no mortality at 5% concentration, while 14g and 17c achieved complete adult kill at 5% with LC50 values of 1.37% (95% CI: 1.15%-1.63%) and 1.64% (95% CI: 1.38%-1.95%), respectively. The critical difference was geometric, not thermodynamic. Active compounds 14g and 17c penetrated the ~20 Å aromatic gorge to position within 2.5-2.8 Å of the catalytic serine (Ser318), forming hydrogen bonds and halogen bonds with the triad. Inactive compounds arrested at 7.0-7.5 Å, trapped in the peripheral anionic site with negligible catalytic residue contact despite favorable overall binding. This 4.5 Å threshold correlated with biological activity…
Read the paper
Related studies
- Chaos and quantum thermalization
- The Dalton quantum chemistry program system
- Cord Blood Leptin and Adiponectin as Predictors of Adiposity in Children at 3 Years of Age: A Prospective Cohort Study
- Quantitative metabolomics by H-NMR and LC-MS/MS confirms altered metabolic pathways in diabetes
- Stable adiabatic quantum batteries
- A novel self-lipid antigen targets human T cells against CD1c(+) leukemias
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.