Discovery of a Novel Inhibitor Structure of <i>Mycobacterium tuberculosis</i> Isocitrate Lyase
Changyuan Duan,
Qihua Jiang,
Xue Jiang,
Hongwei Zeng,
Qiaomin Wu,
Yang Yu,
Xiaolan Yang
Affiliations
Changyuan Duan
Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong Dist, Chongqing 400016, China
Qihua Jiang
College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
Xue Jiang
Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong Dist, Chongqing 400016, China
Hongwei Zeng
Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong Dist, Chongqing 400016, China
Qiaomin Wu
Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong Dist, Chongqing 400016, China
Yang Yu
Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong Dist, Chongqing 400016, China
Xiaolan Yang
Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong Dist, Chongqing 400016, China
Tuberculosis remains a global threat to public health, and dormant Mycobacterium tuberculosis leads to long-term medication that is harmful to the human body. M. tuberculosis isocitrate lyase (MtICL), 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 M. tuberculosis. The aim of this study was to evaluate natural compounds as potential MtICL 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 MtICL, 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 MtICL in vitro and M. smegmatis; daphnetin gave an IC50 of 4.34 μg/mL for the MtICL enzyme and an MIC value of 128 μg/mL against M. smegmatis, 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 MtICL to combat dormant M. tuberculosis.
