Discovery of a Novel Inhibitor Structure of Isocitrate Lyase.

Tuberculosis remains a global threat to public health, and dormant leads to long-term medication that is harmful to the human body. isocitrate lyase (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 . The aim of this study was to evaluate natural compounds as potential 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 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 ICL in vitro and ; daphnetin gave an IC of 4.34 μg/mL for the ICL enzyme and an MIC value of 128 μg/mL against , 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 ICL to combat dormant .