title: Computational analyses of curcuminoid analogs against kinase domain of HER2.
abstract: BACKGROUND
  Human epidermal growth factor receptor 2 (HER2) has an important role in cancer aggressiveness and poor prognosis. HER2 has been used as a drug target for cancers. In particular, to effectively treat HER2-positive cancer, small molecule inhibitors were developed to target HER2 kinase. Knowing that curcumin has been used as food to inhibit cancer activity, this study evaluated the efficacy of natural curcumins and curcumin analogs as HER2 inhibitors using in vitro and in silico studies. The curcumin analogs considered in this study composed of 4 groups classified by their core structure, β-diketone, monoketone, pyrazole, and isoxazole.
  
  
  RESULTS
  In the present study, both computational and experimental studies were performed. The specificity of curcumin analogs selected from the docked results was examined against human breast cancer cell lines. The screened curcumin compounds were then subjected to molecular dynamics simulation study. By modifying curcumin analogs, we found that protein-ligand affinity increases. The benzene ring with a hydroxyl group could enhance affinity by forming hydrophobic interactions and the hydrogen bond with the hydrophobic pocket. Hydroxyl, carbonyl or methoxy group also formed hydrogen bonds with residues in the adenine pocket and sugar pocket of HER2-TK. These modifications could suggest the new drug design for potentially effective HER2-TK inhibitors. Two outstanding compounds, bisdemethylcurcumin (AS-KTC006) and 3,5-bis((E)-3,4-dimethoxystyryl)isoxazole (AS-KTC021 ),were well oriented in the binding pocket almost in the simulation time, 30 ns. This evidence confirmed the results of cell-based assays and the docking studies. They possessed more distinguished interactions than known HER2-TK inhibitors, considering them as a promising drug in the near future.
  
  
  CONCLUSIONS
  The series of curcumin compounds were screened using a computational molecular docking and followed by human breast cancer cell lines assay. Both AS-KTC006 and AS-KTC021 could inhibit breast cancer cell lines though inhibiting of HER2-TK. The intermolecular interactions were confirmed by molecular dynamics simulation studies. This information would explore more understanding of curcuminoid structures and HER2-TK.
authors.forename: Wannarat
authors.initials: W
authors.lastname: Yim-im
authors.affiliation: Institute of Food Research and Product Development, Kasetsart University, 50 Ngam Wong Wan Rd, Chatuchak, Bangkok 10900, Thailand. ifrots@ku.ac.th.
authors.forename: Orathai
authors.initials: O
authors.lastname: Sawatdichaikul
authors.forename: Suwanna
authors.initials: S
authors.lastname: Semsri
authors.forename: Natharinee
authors.initials: N
authors.lastname: Horata
authors.forename: Wanwimon
authors.initials: W
authors.lastname: Mokmak
authors.forename: Sissades
authors.initials: S
authors.lastname: Tongsima
authors.forename: Apichart
authors.initials: A
authors.lastname: Suksamrarn
authors.forename: Kiattawee
authors.initials: K
authors.lastname: Choowongkomon
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D003474:Curcumin; D008024:Ligands; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
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