Structural basis of UDP-N-acetylglucosamine pyrophosphorylase and identification of promising terpenes to control Aedes aegypti

According to the world health organization (WHO) 2020 report, vector borne diseases account for 17 % of all infections with reported 700 thousand death each year. They are of considerable importance to health professionals as they are posing a serious health threat and include dengue fever, Zika fever, chikungunya, yellow fever, and other disease agents. Aedes aegypti serve as a vector for transmitting several of these tropical fevers. In the present study, UDP-N-acetylglucosamine pyrophosphorylase enzyme (Aa-UAP) of A. aegypti which plays a significant contribution in chitin metabolism is targeted with natural terpenes to propose an eco-friendly and novel candidates for the development of new insecticides. The three dimensional Aa-UAP structure was constructed via a comparative homology approach and validated, followed by structure-based virtual screening against 1000 terpenes collected from natural MDP3 and NPACT databases. Top hits were subjected to molecular dynamics (MD) simulations and binding free energies analysis to elucidate complex intermolecular stability and affinity over simulated time. The results demonstrated that Aa-UAP possesses a homodimer state and its active site residues are well conserved. Three compounds (NPACT00138, NPACT00452, and NPACT00839) were prioritized as they are establishing conserved and stable interactions with the active binding-site residues of AaUAP. Conclusively, the reported Aa-UAP specific terpenes could serve as promising leads in order to develop potential insecticides. Importantly, the FDA approved drug NPACT00839 (Paclitaxel) could be used further in the fast-track experimental testing pipeline for biological optimization.

Automated summary

In this study, a novel and eco-friendly candidate for insecticide development targeting the UDP-N-acetylglucosamine pyrophosphorylase enzyme of Aedes aegypti with natural terpenes was proposed. Molecular dynamics simulations and binding free energies analysis revealed three compounds with stable interactions with the active binding-site residues, suggesting potential as insecticide leads. The FDA approved drug NPACT00839 (Paclitaxel) showed promising results and could be further optimized for experimental testing.