Insights into a class of natural eugenol and its optimized derivatives as potential tobacco mosaic virus helicase inhibitors by structure-based virtual screening.

Plant diseases caused by malignant and refractory phytopathogenic viruses have considerably restricted crop yields and quality. To date, drug design targeting functional proteins or enzymes of viruses is an efficient and viable strategy to guide the development of new pesticides. Herein, a series of novel eugenol derivatives targeting the tobacco mosaic virus (TMV) helicase have been designed using structure-based virtual screening (SBVS). Structure-activity relationship indicated that 2 t displayed the most powerful bonding capability (K = 0.2 μM) along with brilliant TMV helicase ATPase inhibitory potency (IC = 141.9 μM) and applausive anti-TMV capability (EC = 315.7 μg/mL), ostentatiously outperforming that of commercial Acyclovir (K = 23.0 μM, IC = 183.7 μM) and Ribavirin (EC = 624.3 μg/mL). Molecular dynamics simulations and docking suggested ligand 2 t was stable and bound in the active pocket of the TMV helicase by multiple interactions. Given these superior properties, eugenol-based derivatives could be considered as the novel potential plant viral helicase inhibitors. Furthermore, this effective and feasible SBVS strategy established a valuable screening platform for helicase-targeted drug development.