title: In silico investigation of potential pyruvate kinase M2 regulators from traditional Chinese medicine against cancers.
abstract: A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted from Lycium chinense Mill. and Abrus precatorius L., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.
authors.affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Kuan-Chung
authors.initials: KC
authors.lastname: Chen
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; Department of Anesthesiology, China Medical University Hospital, Taichung 40447, Taiwan.
authors.forename: Kuen-Bao
authors.initials: KB
authors.lastname: Chen
authors.affiliation: Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan ; Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung 40402, Taiwan.
authors.forename: Calvin Yu-Chian
authors.initials: CY
authors.lastname: Chen
mesh_terms: D001216:Asparagine / Q000031:analogs & derivatives / Q000737:chemistry; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019295:Computational Biology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D008516:Medicine, Chinese Traditional; D008565:Membrane Proteins / Q000737:chemistry*; D008938:Mitosis; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy*; D011487:Protein Conformation; D013963:Thyroid Hormones / Q000737:chemistry*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D001216:Asparagine; D002352:Carrier Proteins; D008024:Ligands; D008239:Lysine; D008565:Membrane Proteins; D013963:Thyroid Hormones; D014364:Tryptophan; D000097810:Thyroid Hormone-Binding Proteins; C000595384:saussureamine C; C021733:precatorine
references.citation: PLoS One. 2012;7(11):e50087
references.pmid: 23209648
references.citation: J Chem Theory Comput. 2008 Mar;4(3):435-47
references.pmid: 26620784
references.citation: Nature. 2008 Mar 13;452(7184):230-3
references.pmid: 18337823
references.citation: PLoS Comput Biol. 2011 Oct;7(10):e1002189
references.pmid: 22022246
references.citation: Chem Biol. 2012 Sep 21;19(9):1187-98
references.pmid: 22999886
references.citation: Biochem J. 2001 Feb 1;353(Pt 3):417-39
references.pmid: 11171037
references.citation: Sci Rep. 2013;3:844
references.pmid: 23378894
references.citation: J Biomol Struct Dyn. 2012;30(6):662-83
references.pmid: 22731403
references.citation: J Comput Chem. 2011 Aug;32(11):2359-68
references.pmid: 21541964
references.citation: Mol Biosyst. 2011 Sep;7(9):2711-9
references.pmid: 21796302
references.citation: Curr Top Med Chem. 2013;13(9):965-88
references.pmid: 23651478
references.citation: Drug Discov Today. 2013 Oct;18(19-20):910-5
references.pmid: 23643489
references.citation: Nat Chem Biol. 2012 Oct;8(10):839-47
references.pmid: 22922757
references.citation: Biochim Biophys Acta. 2010 Apr;1804(4):996-1010
references.pmid: 20100603
references.citation: J Mol Graph Model. 2003 Jan;21(4):289-307
references.pmid: 12479928
references.citation: J Mol Graph Model. 2010 Aug 24;29(1):21-31
references.pmid: 20471294
references.citation: Chem Biol Drug Des. 2011 Oct;78(4):679-88
references.pmid: 21801310
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: J Biomol Struct Dyn. 2013;31(11):1219-35
references.pmid: 23146021
references.citation: PLoS One. 2011 Jan 06;6(1):e15939
references.pmid: 21253603
references.citation: PLoS One. 2010 May 07;5(5):e10504
references.pmid: 20498699
references.citation: Mol Cell. 2014 Jan 9;53(1):75-87
references.pmid: 24316223