2. Academic Validation
  3. Discovery and characterization of novel ATP citrate lyase inhibitors from natural products by a luminescence-based assay

Discovery and characterization of novel ATP citrate lyase inhibitors from natural products by a luminescence-based assay

  • Chem Biol Interact. 2022 Nov 1;367:110199. doi: 10.1016/j.cbi.2022.110199.
Pan Wang 1,  Xingrong Peng 2,  Tao Hou 3,  Fangfang Xu 4,  Han Zhou 3,  Yancheng Yu 4,  Minghua Qiu 2,  Yanfang Liu 3,  Yaopeng Zhao 3,  Zhimou Guo 3,  Jixia Wang 5,  Xinmiao Liang 6
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China; University of Chinese Academy of Sciences, Beijing, 100000, China.
  • 2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
  • 3 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China; Jiangxi Provincial Key Laboratory for Pharmacodynamic Material Basis of Traditional Chinese Medicine, Ganjiang Chinese Medicine Innovation Center, Nanchang, 330000, China.
  • 4 Jiangxi Provincial Key Laboratory for Pharmacodynamic Material Basis of Traditional Chinese Medicine, Ganjiang Chinese Medicine Innovation Center, Nanchang, 330000, China.
  • 5 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China; Jiangxi Provincial Key Laboratory for Pharmacodynamic Material Basis of Traditional Chinese Medicine, Ganjiang Chinese Medicine Innovation Center, Nanchang, 330000, China. Electronic address: jxwang@dicp.ac.cn.
  • 6 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China; Jiangxi Provincial Key Laboratory for Pharmacodynamic Material Basis of Traditional Chinese Medicine, Ganjiang Chinese Medicine Innovation Center, Nanchang, 330000, China. Electronic address: liangxm@dicp.ac.cn.
PMID: 36174740 DOI: 10.1016/j.cbi.2022.110199
Abstract

ATP Citrate Lyase (ACLY) is a key Enzyme in glucolipid metabolism with therapeutic prospect for treating hyperlipidemia and various cancers. Much effort has been put into discovering ACLY inhibitors. However, current screening approaches have limitations in sensitivity, portability and high-throughput. To develop a general screening assay, we investigated series of conditions affecting the enzymatic reaction based on the ADP-Glo luminescence assay. Bovine serum albumin (0.001%) added triggered strong and stable fluorescence signal. The optimized assay was validated and applied to screen our natural product library. Two novel inhibitors were identified with IC50 values of 3.86 ± 0.62 μM (2) and 15.48 ± 2.51 μM (4). Their aggregations and target specificities were also examined. 2 was characterized as a noncompetitive inhibitor of ACLY, while 4 was a competitive inhibitor of CoA, which was also elucidated by docking studies. In Anticancer activity evaluation, 2 with higher inhibition potency did not exhibit Anticancer effect, probably owing to its insufficient cell-permeability. 4 showed moderate inhibition in the proliferation of A549 and PC3 cells. This study not only developed a general approach for ACLY inhibitor discovery, but also identified a new scaffold ACLY inhibitor, which could be served as a hit compound in drug design.

Keywords

ACLY inhibitor; High-throughput screening; Inhibition profiles; Natural products.

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