Structural studies on azadirachtin targeting the glucuronosyltransferase from lymphatic filariasis and its inhibition

Abstract

Background and Aims: Brugia malayi, Brugia timori, and Wuchereria bancrofti are parasitic worms that cause lymphatic filariasis, also known as elephantiasis in some parts of the world. Because no effective vaccines and current treatments have adverse pharmacological properties, this condition has sparked much interest in the drug discovery community. This research aims to assess the efficacy of azadirachtin against a possible therapeutic target, intestine glucuronosyltransferase protein, in treating and preventing lymphatic filariasis. Methods: I-Tasser was used to create the protein, Uniprot was used to collect its FASTA sequences, and Galaxy Refine was used to refine the protein model. The protein 3D model was tested using PROCHECK and ERRAT. We used PubChem to get the three-dimensional structure of the azadirachtin ligand molecules. To study the toxicity profiles and pharmacokinetics, researchers employ SwissADME. Molecular docking studies were conducted using the AutoDock tool, and Pymol viewer was used to observe the interactions between the target protein and the ligand molecules. Results: The azadirachtin compound has a satisfactory range of pharmacokinetic parameters in terms of its absorption, distribution, metabolism, and excretion. When compared to the currently existing drug Diethylcarbamazine, molecular docking studies indicate that the azadirachtin molecule binds with the intestinal glucuronosyltransferase proteins of Brugia timori, Wuchereria bancrofti, and Brugia malayi strongly. Conclusions: In sum, our understanding of the mechanism by which azadirachtin, a traditional component derived from plants, inhibits intestinal glucuronosyltransferase protein is enhanced, and this could pave the way for the development of new targeted anti-filarial agents.