title: Design, synthesis, and docking studies of peptidomimetics based on HER2-herceptin binding site with potential antiproliferative activity against breast cancer cell lines.
abstract: Epidermal growth factor receptor kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 occurs frequently in breast, ovarian, and lung cancers, making it an important therapeutic target in the treatment of cancer. Blocking HER2-mediated signaling with antibodies or small molecules has been shown to be effective in inhibiting cell growth. After analyzing the crystal structure of the HER2-herceptin complex, several peptidomimetics (HERP5, 6, and 7) were designed to inhibit HER2-mediated signaling for cell growth. We have used an in silico screening method to investigate the chemical diversity of the designed compounds. autodock software was used to dock the different analogs of HERP5 and HERP7 with HER2 protein extracellular domain. A total of 53 compounds were docked to HER2 protein, and their binding modes were analyzed in terms of docking energy, hydrogen bonding, and hydrophobic interactions. Compounds that exhibited low-energy docked structures were chosen for chemical synthesis and biological activity. Two of the compounds (HERP5 and HERP7) exhibited antiproliferative activity, with IC(50) values of 0.396 microm and 0.143 microm, respectively, against SKBR-3 cell lines (breast cancer cell lines) that overexpress HER2 protein.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71201, USA. jois@ulm.edu
authors.forename: Seetharama
authors.initials: S
authors.lastname: Satyanarayanajois
authors.forename: Stephanie
authors.initials: S
authors.lastname: Villalba
authors.forename: Liu
authors.initials: L
authors.lastname: Jianchao
authors.forename: Go Mei
authors.initials: GM
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D007529:Isoflavones; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007529:Isoflavones; D010455:Peptides; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C576978:7-(O)-carboxymethyl daidzein N-t-Boc-hexylenediamine conjugate
references.citation: Cancer Lett. 2008 Oct 8;269(2):243-61
references.pmid: 18550275
references.citation: Endocr Relat Cancer. 2002 Dec;9(4):249-66
references.pmid: 12542402
references.citation: J Biol Chem. 2005 Jan 7;280(1):54-63
references.pmid: 15507452
references.citation: Bioorg Med Chem Lett. 2005 Nov 1;15(21):4774-9
references.pmid: 16111887
references.citation: Cancer Res. 2001 Jun 15;61(12):4744-9
references.pmid: 11406546
references.citation: J Biol Chem. 2002 Aug 2;277(31):28330-9
references.pmid: 12011054
references.citation: J Med Chem. 2003 Jan 2;46(1):49-63
references.pmid: 12502359
references.citation: Br J Surg. 2002 Mar;89(3):262-71
references.pmid: 11872048
references.citation: Cancer Res. 2001 Dec 15;61(24):8887-95
references.pmid: 11751413
references.citation: Pharmacol Ther. 1999 May-Jun;82(2-3):241-50
references.pmid: 10454201
references.citation: N Engl J Med. 2001 Mar 15;344(11):783-92
references.pmid: 11248153
references.citation: J Clin Oncol. 1999 Sep;17(9):2639-48
references.pmid: 10561337
references.citation: Nat Rev Cancer. 2005 May;5(5):341-54
references.pmid: 15864276
references.citation: Semin Oncol. 2004 Oct;31(5 Suppl 10):6-13
references.pmid: 15490369
references.citation: J Immunol. 2007 Jul 1;179(1):472-82
references.pmid: 17579068
references.citation: Clin Cancer Res. 2003 Nov 1;9(14):5078-84
references.pmid: 14613984
references.citation: J Med Chem. 1997 Jun 20;40(13):2085-101
references.pmid: 9207949
references.citation: Oncol Rep. 2005 Jan;13(1):133-7
references.pmid: 15583814
references.citation: Nature. 2003 Feb 13;421(6924):756-60
references.pmid: 12610629
references.citation: Oncogene. 2000 Dec 27;19(56):6550-65
references.pmid: 11426640
references.citation: J Comput Chem. 2007 Apr 30;28(6):1145-52
references.pmid: 17274016
references.citation: Oncogene. 2003 Sep 29;22(42):6570-8
references.pmid: 14528282
references.citation: Mol Cell. 2003 Sep;12(3):541-52
references.pmid: 14527402
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Oncologist. 2004;9(1):58-67
references.pmid: 14755015
references.citation: J Med Chem. 2003 Oct 23;46(22):4657-68
references.pmid: 14561085
references.citation: Cancer Cell. 2004 Apr;5(4):317-28
references.pmid: 15093539
references.citation: Cancer Res. 1988 Feb 1;48(3):589-601
references.pmid: 3335022
references.citation: Cancer Cell. 2002 Aug;2(2):127-37
references.pmid: 12204533
references.citation: Cancer Res. 2004 Jun 1;64(11):3958-65
references.pmid: 15173008
references.citation: Oncogene. 2004 Jan 29;23(4):883-93
references.pmid: 14661053