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.
Graphical Abstract
Medicinal Chemistry
Title:Integrated In Silico-In Vitro Discovery of Lung Cancer-related Tumor Pyruvate Kinase M2 (PKM2) Inhibitors
Volume: 12 Issue: 7
Author(s): Xiangyun Ye, Yinjia Sun, Yunhua Xu, Zhiwei Chen and Shun Lu
Affiliation:
Keywords: Tumor pyruvate kinase M2, kinase inhibitor, virtual screening, lung cancer.
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.
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Cite this article as:
Ye Xiangyun, Sun Yinjia, Xu Yunhua, Chen Zhiwei and Lu Shun, Integrated In Silico-In Vitro Discovery of Lung Cancer-related Tumor Pyruvate Kinase M2 (PKM2) Inhibitors, Medicinal Chemistry 2016; 12 (7) . https://dx.doi.org/10.2174/1573406412666160307151535
DOI https://dx.doi.org/10.2174/1573406412666160307151535 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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