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IDENTIFICATION OF POTENT INHIBITORS OF UDP-GALACTOPYRANOSE MUTASE FOR FILARIAL NEMATODES USING AN IN SILICO APPROACH

Abstract

Karthik L, Wubliker Dessie Lemma, Gunasekaran K

Lymphatic filariasis, commonly known as elephantiasis, is a neglected tropical disease. Infection occurs when filarial parasites are transmitted to humans through mosquitoes. In its most obvious manifestations, lymphatic filariasis causes enlargement of the entire leg or arm, the genitals, vulva and breasts. It has been identified by the World Health Organization (WHO) as the second leading cause of permanent and long-term disability (WHO 1997a, b). Current filariasis control strategies are not entirely successful and filarial infections are on the rise. Therefore novel chemotherapeutics and vaccines are urgently needed. UDP-galactopyranose mutase (UGM) is a flavoenzyme that catalyzes the conversion of UDP-galactopyranose to UDP-galactofuranose, which is a central reaction in galactofuranose biosynthesis. The importance of UGM for the viability of many pathogens and its absence in humans makes UGM a potential drug target. In this study, UGM from the parasitic nematode Brugia malayi has been considered as a target during in silico drug design of potent filarial inhibitor. As there are no crystal structures are available for Brugia malayi's UGM, homology modelling approach has been employed for determining the 3D structure. A library of 55 compounds has been screened against the target structure using rigid docking. Based on the various parameters from the initial docking results about 5 compounds were filtered out and were further subjected for induced fit docking and the detailed results are reported. In addition to this, the existing anti-filarial drugs have also been subjected for induced fit docking with the Brugia malayi’s UGM. The results show that the reported compounds have not only exhibited greater docking score and energy but also possessed reliable hydrogen bonding interactions with the active site key residues. As no anti-filarial compounds are available, compounds reported in this study can be optimized further and can be developed into potent drugs in combating lymphatic filariasis.

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