Find in Library

Tuberculosis remains a global threat to public health, and dormant <i>Mycobacterium tuberculosis</i> leads to long-term medication that is harmful to the human body. <i>M. tuberculosis</i> isocitrate lyase (<i>Mt</i>ICL), which is absent in host cells, is a key rate-limiting enzyme of the glyoxylic acid cycle and is essential for the survival of dormant <i>M. tuberculosis</i>. The aim of this study was to evaluate natural compounds as potential <i>Mt</i>ICL inhibitors through docking and experimental verification. Screening of the TCMSP database library was done using Discovery Studio 2019 for molecular docking and interaction analysis, with the putative inhibitors of <i>Mt</i>ICL, 3-BP, and IA as reference ligands. Daphnetin (MOL005118), with a docking score of 94.8 and -CDOCKER interaction energy of 56 kcal/mol, was selected and verified on <i>Mt</i>ICL in vitro and <i>M. smegmatis</i>; daphnetin gave an IC₅₀ of 4.34 μg/mL for the <i>Mt</i>ICL enzyme and an MIC value of 128 μg/mL against <i>M. smegmatis</i>, showing enhanced potential in comparison with 3-BP and IA. The interactions and essential amino acid residues of the protein were analyzed. In summary, natural daphnetin may be a promising new skeleton for the design of inhibitors of <i>Mt</i>ICL to combat dormant <i>M. tuberculosis</i>.