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Integrated In Silico-In Vitro Discovery of Lung Cancer-related Tumor Pyruvate Kinase M2 (PKM2) Inhibitors

[ Vol. 12 , Issue. 7 ]

Author(s):

Xiangyun Ye, Yinjia Sun, Yunhua Xu, Zhiwei Chen and Shun Lu   Pages 613 - 620 ( 8 )

Abstract:


Background: The tumor pyruvate kinase M2 (PKM2) is involved in the glycolytic pathway of lung cancer and targeting this kinase has been observed to radiosensitize non-small cell lung cancer (NSCLC).

Objective: An integration of in silico virtual screening and in vitro kinase assay was described to discover novel PKM2 inhibitors from a candidate library containing >400,000 commercially available compounds.

Method: The method is a stepwise screening scheme that first used empirical strategies to fast exclude those undruggable compounds in the library and then employed molecular docking and molecular dynamics (MD)-based rescoring to identify few potential hits. Subsequently, the computational findings were substantiated using a standard kinase assay protocol.

Results: Four compounds, i.e. nalidixic acid, indoprofen, hematoxylin and polydatin, were identified to inhibit PKM2 kinase at micromolar level, with IC50 values of 53, 21, 340 and 128 M, respectively.

Conclusion: Structural analysis revealed that hydrogen bonds, salt bridges, - stacking and hydrophobic forces co-confer high stability and strong specificity to PKM2–inhibitor binding.

Keywords:

Tumor pyruvate kinase M2, kinase inhibitor, virtual screening, lung cancer.

Affiliation:

Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 Huaihai West Road, Shanghai 200030, China.

Graphical Abstract:



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