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.