In silico screening of flavonoid-based inhibitors targeting UDP-galactopyranose mutase of Brugia malayi for lymphatic filariasis drug design.

Lymphatic filariasis (LF) is a vector-borne disease caused by parasitic roundworms, such as Wuchereria bancrofti, Brugia malayi, and Brugia timori, transmitted through mosquito vectors. Drugs such as albendazole, ivermectin, and diethylcarbamazine are used to treat LF; however, they mainly act against the microfilarial stage and have limited effect on the adult worms. So, it is time to identify or design a more efficient drug against the LF. Targeting the UDP-galactopyranose mutase (UGM) enzyme offers an effective strategy for treating lymphatic filariasis, as this enzyme is absent in mammals. The structure of B. malayi UDP-galactopyranose mutase (BmUGM) was modeled, and a library of 2845 flavonoid-based analogues was retrieved from the PubChem database. Structure-based virtual screening was conducted to target the substrate-binding site and identify potential lead compounds. The best docking score of the identified ligand molecules ranges between -8.98 and -11.358 kcal/mol. Molecular dynamics (MD) simulations were performed in triplicate on the screened protein-ligand complexes, as well as the control compound, galP(S), over a 200 ns timescale to assess the stability of the interactions. Molecular docking and binding free energy calculations identified ligand5 as exhibiting strong and stable binding comparable to the control. Complementary DFT analysis and ADMET predictions further highlighted ligand 5's favourable chemical reactivity and pharmacokinetic properties, indicating it as a promising candidate for further experimental validation in the development of novel therapeutics against all stages of LF infection.