Homology Modelling and Molecular Docking of Some Natural Compounds as Inhibitors of Anopheles gambiae Heat Shock Protein 70KDa and Bifunctional Glutamyl/prolyl-tRNA Synthetase
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Abstract
Malaria has remained a global concern, primarily caused by Plasmodium falciparum, which is transmitted through the bite of female Anopheline mosquitoes. Although several insecticides have been developed to target the vector, resistance to currently available insecticides necessitate the development of novel, natural insecticides with little or no negative impact on the ecosystem towards the eradication of malaria. Natural product-derived compounds have shown promising effects in combating the disease-carrying vector. Homology modeling of the Anopheles gambiae (A. gambiae) heat shock protein 70KDa (AgHSP70KDa) and bifunctional glutamyl/prolyl-tRNA synthetase (AgEPRS) was carried out using the SWISSMODEL server, and the generated 3-dimensional (3D) structures were refined using the Chiron webserver for energy minimization. The structures were further validated using PROCHECK to verify and validate the 3D conformation. The top five compounds based on binding affinity, were then subjected to ADME-Tox profiling using SwissADME and ORISIS. The docking results reveal that compounds, particularly sesamin (-7.4 kcal/mol) exhibited a better binding affinity for AgEPRS compared to the control, halofuginone, which showed a binding affinity of -6.4 kcal/mol. Additionally, sesamin showed superior affinity of -5.5 kcal/mol against AgHSP70KDa when compared to the control geldanamycin, which had a binding affinity of -4.9 kcal/mol. However, violacein (control) demonstrated a stronger affinity of -5.6 kcal/mol for AgHSP70KDa compared to sesamin. Violacein and sesamin form unique interactions with specific amino acids and engage with the active sites of AgHSP70KDa and AgEPRS through a range of bonds, including hydrogen bonds, Pi-Alkyl contacts, and Pi-Cation/Anion interactions. The research highlights the potential of natural compounds to act as potent inhibitors against A. gambiae proteins. Further biological validation of these compounds against AgHSP70KDa and AgEPRS is essential. This will ultimately contribute to the development of novel, target-specific insecticides against A. gambiae.
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