Molecular interaction studies of thymol via molecular dynamic simulations and free energy calculations using multi-target approach against Aedes aegypti proteome to decipher its role as mosquito repellent

Aedes aegypti (A. aegypti) is the principal vector for several diseases and despite having synthetic repellents to curb its feeding and transmission, they pose a threat to humans upon chronic use. Therefore, this study explores natural alternative thymol, via both structural and molecular binding properties against whole proteome targets of A. using a multi-target approach. Properties of thymol were studied using ProTox-II to determine the toxicity class. A preliminary screening of the proteome of A. aegypti was performed using existing microarray data analysis, conserved domain studies and protein modelling to narrow down the target categories. RaptorX standalone high-computing server was utilised for 309 protein structure modelling. Molecular docking was performed for 20 shortlisted protein categories against thymol, and top three docked complexes were simulated at 100 ns. Results showed that thymol belonged to class 4 low-toxicity, and molecular docking and 100 ns simulations in dynamic environment revealed stable complexes of thymol with glutathione-S-transferase (GST), octopamine receptor and glutamate-gated chloride channels (GGCC). Free energy binding via molecular mechanics revealed thymol with GST and GGCC to be stable. Our multi-target study presents insights into the molecular binding events that take place when thymol binds to newly identified A. aegypti targets.