title: Dual-inhibitors of STAT5 and STAT3: studies from molecular docking and molecular dynamics simulations.
abstract: Although molecularly targeted therapy with imatinib has improved treatments of chronic myeloid leukemia (CML), clinical resistance gradually develops in patients with accelerated or blast phase CML. The inability of imatinib to cure CML suggests that inactivation of BCR-ABL kinase activity alone is not sufficient to control the disease. Aberrant STAT signaling and constitutive STAT5 or STAT3 activation are frequently found in both acute and chronic leukemia. Constitutive activation of STAT5 and STAT3 are associated with imatinib resistance on leukemia cells. Development of drugs targeting SH2 domains of STAT5 and STAT3 provides a novel strategy for the treatment of the imatinib-resistant CML. Here, molecular docking and molecular dynamics simulations were used to investigate the interactions of the drugs targeting STAT3 and STAT5 receptors at molecular level. The calculated binding free energies are consistent with the ranking of the experimental affinities and our simulations also explained their differences in binding energy. Then virtual screening based on molecular docking and molecular dynamics was applied to screen a set of ~1500 compounds for dual inhibitors of the SH2 domains of STAT5 and STAT3. Three top score compounds obtained in virtual screening were compound 660, 304, and 561. Results show that the three predicted dual-inhibitors are well fitted within the two binding domains and are predicted to present improved STAT5 and STAT3 SH2 inhibitory activity.
authors.affiliation: Department of Chemistry and Chemical Engineering, Taiyuan Institute of Technology, Taiyuan, 030008, China.
authors.forename: Shengjuan
authors.initials: S
authors.lastname: Shao
authors.forename: Rilei
authors.initials: R
authors.lastname: Yu
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Yu
authors.forename: Yanni
authors.initials: Y
authors.lastname: Li
mesh_terms: D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013816:Thermodynamics; D014584:User-Computer Interface; D018909:src Homology Domains
chemical_list: D008024:Ligands; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor
references.citation: PLoS Comput Biol. 2011 Mar;7(3):e1002011
references.pmid: 21390272
references.citation: J Immunol. 2003 Oct 1;171(7):3863-71
references.pmid: 14500688
references.citation: J Mol Model. 2013 Feb;19(2):871-8
references.pmid: 23086458
references.citation: Proteins. 2002 Nov 1;49(2):181-90
references.pmid: 12210999
references.citation: Bioorg Med Chem Lett. 2008 Jan 1;18(1):391-5
references.pmid: 18006313
references.citation: Mol Cancer. 2010 Aug 16;9:217
references.pmid: 20712901
references.citation: ACS Med Chem Lett. 2011 Jan 13;2(1):79-84
references.pmid: 21243039
references.citation: Ann Oncol. 2006 Sep;17 Suppl 10:x274-9
references.pmid: 17018738
references.citation: Expert Opin Biol Ther. 2006 Mar;6(3):231-41
references.pmid: 16503733
references.citation: ChemMedChem. 2011 Aug 1;6(8):1459-70
references.pmid: 21618433
references.citation: Oncotarget. 2011 Jun;2(6):518-24
references.pmid: 21680956
references.citation: J Chem Inf Model. 2012 Oct 22;52(10):2715-29
references.pmid: 22998323
references.citation: Science. 2001 Aug 3;293(5531):876-80
references.pmid: 11423618
references.citation: J Comput Chem. 2005 Dec;26(16):1668-88
references.pmid: 16200636
references.citation: J Biol Chem. 2005 Dec 9;280(49):40782-7
references.pmid: 16192273
references.citation: J Comput Chem. 2004 Jul 15;25(9):1157-74
references.pmid: 15116359
references.citation: Blood. 2011 Mar 24;117(12):3409-20
references.pmid: 21220747
references.citation: Biopolymers. 2008;90(1):69-79
references.pmid: 18058821
references.citation: Mol Cancer Ther. 2004 Mar;3(3):261-9
references.pmid: 15026546
references.citation: Nature. 1998 Jul 9;394(6689):145-51
references.pmid: 9671298
references.citation: J Med Chem. 2012 Feb 9;55(3):1047-55
references.pmid: 22148584
references.citation: J Biol Chem. 2001 Nov 30;276(48):45443-55
references.pmid: 11579100
references.citation: Blood. 2000 Aug 1;96(3):1070-9
references.pmid: 10910924
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7391-6
references.pmid: 17463090
references.citation: Biochemistry. 2000 Mar 7;39(9):2201-7
references.pmid: 10694385
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4700-5
references.pmid: 15781862
references.citation: Leuk Res. 2010 Oct;34(10):1255-68
references.pmid: 20537386
references.citation: J Am Chem Soc. 2001 Jun 6;123(22):5221-30
references.pmid: 11457384
references.citation: Curr Opin Struct Biol. 2001 Oct;11(5):560-6
references.pmid: 11785756
references.citation: J Med Chem. 2013 Sep 12;56(17):6560-72
references.pmid: 23688234
references.citation: Leukemia. 2011 Jan;25(1):7-22
references.pmid: 21102425
references.citation: Neoplasia. 2010 Jan;12(1):39-50
references.pmid: 20072652
references.citation: Blood Rev. 2011 Nov;25(6):279-90
references.pmid: 21982419
references.citation: Chem Biol. 2006 Nov;13(11):1235-42
references.pmid: 17114005
references.citation: J Mol Recognit. 2011 Mar-Apr;24(2):254-65
references.pmid: 21360612
references.citation: Biochem Pharmacol. 2010 May 15;79(10):1398-409
references.pmid: 20067773
references.citation: N Engl J Med. 2003 Mar 13;348(11):994-1004
references.pmid: 12637609
references.citation: Clin J Oncol Nurs. 2009 Oct;13(5):523-34
references.pmid: 19793709
references.citation: Oncogene. 2007 Apr 12;26(17):2435-44
references.pmid: 17043651
references.citation: Nat Med. 2005 Jun;11(6):595-6
references.pmid: 15937466
references.citation: Mol Biosyst. 2012 Nov;8(11):3049-60
references.pmid: 22990663
references.citation: J Chem Inf Model. 2011 Jan 24;51(1):69-82
references.pmid: 21117705
references.citation: Blood. 2007 Mar 1;109(5):2147-55
references.pmid: 17090651
references.citation: Mol Cancer Ther. 2008 Oct;7(10):3169-75
references.pmid: 18852120
references.citation: Anal Biochem. 2004 Jul 1;330(1):114-8
references.pmid: 15183768
references.citation: Nature. 1996 Feb 15;379(6566):645-8
references.pmid: 8628398
references.citation: EMBO Mol Med. 2010 Mar;2(3):98-110
references.pmid: 20201032
references.citation: J Biol Chem. 2010 Jul 9;285(28):21446-57
references.pmid: 20452982
references.citation: Crit Rev Oncol Hematol. 2011 Apr;78(1):33-44
references.pmid: 20570172
references.citation: Chembiochem. 2008 Mar 25;9(5):723-7
references.pmid: 18247434
references.citation: Anticancer Res. 2005 May-Jun;25(3B):1841-50
references.pmid: 16158916
references.citation: Blood. 2003 Apr 15;101(8):2940-54
references.pmid: 12480704
references.citation: Eur J Haematol. 2011 Nov;87(5):381-93
references.pmid: 21815933
references.citation: Bioorg Med Chem Lett. 2008 Sep 15;18(18):4988-92
references.pmid: 18768317
references.citation: J Mol Graph Model. 2010 Feb 26;28(6):555-68
references.pmid: 20056466