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

Author(s): Xiangyun Ye , Yinjia Sun , Yunhua Xu , Zhiwei Chen , Shun Lu .

Journal Name: Medicinal Chemistry

Volume 12 , Issue 7 , 2016

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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.

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Article Details

VOLUME: 12
ISSUE: 7
Year: 2016
Page: [613 - 620]
Pages: 8
DOI: 10.2174/1573406412666160307151535
Price: $58

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