Eksplorasi Aktivitas Flavonoid Daun Sukun (Artocarpus altilis) sebagai Inhibitor DsbA Mycobacterium tuberculosis Patogen Secara In Silico

Abstract

Tuberculosis has emerged as a significant contributor to the global healthcare burden, caused by antimicrobial resistance and the evolution mechanisms to manipulate host immune signaling responses. New therapeutic strategies are urgently needed to combat the growing threat of drug-resistant tuberculosis. The enzyme disulfide bond-forming pathways of Mycobacterium tuberculosis (MtDsbA) are potential targets for the development of anti-virulence inhibitors because of their importance in the production of various virulence factors essential for bacterial pathogenesis. In this study, the MtDsbA inhibitory activity of flavonoids from breadfruit leaves (Artocarpus Altilis) and their potential as anti-virulence drugs were investigated using molecular docking, drug-likeness analysis, and ADMET analysis. The four most active flavonoids, namely, 2-Geranyl-2’,3,4,4’-tetrahydroxydihydrochalcone (12), artoindonesianin (14), quercetin (8), cycloaltilisin (5), and artocarpin (10), may potentially inhibit the allosteric site of MtDsbA effectively. The interaction with the residues Glu96, Glu147, and Lys159 in flavonoids indicates their ability to inhibit the buried water network essential for MtDsbA catalytic activity. Drug-likeness and ADMET analyses showed that flavonoids require modification of their prenyl groups to reduce their lipophilicity and increase their permeability. Together, these results show that flavonoids from breadfruit leaves have the potential to inhibit the allosteric sites of MtDsbA and act as anti-virulence inhibitors.