Abstract
Neonicotinoids are synthetic nicotine-like compounds extensively used globally as insecticides for agricultural and urban purposes. Neonicotinoid-contaminated produce is a major public health concern worldwide. Limited epidemiological studies have shown an association of neonicotinoid exposure with abnormal semen analysis. This study aimed to elucidate the potential disruption of the androgen receptor (AR) by eight common neonicotinoids, including imidacloprid (IMI), acetamiprid, clothianidin, thiamethoxam, dinotefuran, thiacloprid (THI), nitenpyram, and nithiazine using docking and molecular dynamics (MD) simulation. The results showed good binding strength of all compounds (except THI) with AR, as indicated by high binding energy, high binding affinity, and number of bonding interactions. The results of MD simulation supported the conformational stability and structural dynamic behavior of the AR-IMI (receptor-neonicotinoid) complex upon binding. This was indicated by root mean square deviation showing stability of the complex; the root mean square fluctuation showing minimized residual fluctuations upon binding; the radius of gyration showing greater compactness of the protein structure; the solvent-accessible surface area showing no changes upon binding; and the Gibbs funnel energy of the landscape showing a stable conformation state with minimum energy and slight change in size and position of the sampled energy basin of the AR, with a stable equilibrium. Taken together, the structural dynamics results showed that neonicotinoids are bound stably in the same ligand-binding domain of the AR as the native ligand testosterone. This may perturb the natural binding of testosterone with the AR and potentially disrupt downstream signaling and biological pathways, leading to male reproductive dysfunction.