title: Identification, design and bio-evaluation of novel Hsp90 inhibitors by ligand-based virtual screening.
abstract: Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC50 value 1.61±0.28 μM and 2.83±0.67 μM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: JianMin
authors.initials: J
authors.lastname: Jia
authors.forename: XiaoLi
authors.initials: X
authors.lastname: Xu
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: XiaoKe
authors.initials: X
authors.lastname: Guo
authors.forename: MingYe
authors.initials: M
authors.lastname: Zhang
authors.forename: MengChen
authors.initials: M
authors.lastname: Lu
authors.forename: LiLi
authors.initials: L
authors.lastname: Xu
authors.forename: JinLian
authors.initials: J
authors.lastname: Wei
authors.forename: Jia
authors.initials: J
authors.lastname: Zhu
authors.forename: ShengLie
authors.initials: S
authors.lastname: Zhang
authors.forename: ShengMiao
authors.initials: S
authors.lastname: Zhang
authors.forename: HaoPeng
authors.initials: H
authors.lastname: Sun
authors.forename: QiDong
authors.initials: Q
authors.lastname: You
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands
references.citation: Anal Biochem. 1988 Mar;169(2):312-8
references.pmid: 2968057
references.citation: J Chem Inf Model. 2012 May 25;52(5):1356-66
references.pmid: 22545675
references.citation: Exp Biol Med (Maywood). 2010 Mar;235(3):278-89
references.pmid: 20404045
references.citation: J Mol Biol. 1997 Apr 4;267(3):727-48
references.pmid: 9126849
references.citation: J Med Chem. 2012 Sep 27;55(18):7978-87
references.pmid: 22928876
references.citation: J Mol Graph Model. 2008 Apr;26(7):1160-8
references.pmid: 18061500
references.citation: Trends Mol Med. 2004 Feb;10(2):47-51
references.pmid: 15106614
references.citation: Bioorg Med Chem Lett. 2005 Dec 1;15(23):5197-201
references.pmid: 16213716
references.citation: Expert Opin Biol Ther. 2002 Jan;2(1):3-24
references.pmid: 11772336
references.citation: Curr Opin Pharmacol. 2008 Aug;8(4):370-4
references.pmid: 18644253
references.citation: Anal Biochem. 2000 Mar 15;279(2):248-50
references.pmid: 10706796
references.citation: Nat Rev Cancer. 2005 Oct;5(10):761-72
references.pmid: 16175177
references.citation: Exp Biol Med (Maywood). 2003 Feb;228(2):111-33
references.pmid: 12563018
references.citation: J Med Chem. 2008 Jan 24;51(2):196-218
references.pmid: 18020435
references.citation: Biochem J. 1994 Mar 1;298 ( Pt 2):395-401
references.pmid: 8135747
references.citation: Clin Cancer Res. 2009 Jan 1;15(1):9-14
references.pmid: 19118027
references.citation: Cancer Chemother Pharmacol. 2005 Dec;56(6):637-47
references.pmid: 15986212
references.citation: Cancer Chemother Pharmacol. 2005 Jan;55(1):21-32
references.pmid: 15338192
references.citation: Anticancer Agents Med Chem. 2008 Oct;8(7):761-82
references.pmid: 18855578
references.citation: Biochem J. 2008 Mar 15;410(3):439-53
references.pmid: 18290764
references.citation: Nature. 2003 Sep 25;425(6956):407-10
references.pmid: 14508491
references.citation: Clin Cancer Res. 2008 Dec 1;14(23):7940-6
references.pmid: 19047126
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6704-11
references.pmid: 18927314
references.citation: J Chem Inf Model. 2009 Nov;49(11):2419-28
references.pmid: 19852439
references.citation: J Med Chem. 2009 Aug 13;52(15):4794-809
references.pmid: 19610616
references.citation: J Med Chem. 2010 Oct 28;53(20):7280-6
references.pmid: 20608738
references.citation: J Med Chem. 2006 Jul 27;49(15):4606-15
references.pmid: 16854066
references.citation: Drug Discov Today. 2004 Oct 15;9(20):881-8
references.pmid: 15475321
references.citation: Nat Rev Mol Cell Biol. 2004 Oct;5(10):781-91
references.pmid: 15459659
references.citation: Trends Mol Med. 2004 Jun;10(6):283-90
references.pmid: 15177193
references.citation: J Med Chem. 1995 Sep 15;38(19):3813-20
references.pmid: 7562912
references.citation: Cancer Cell. 2003 Mar;3(3):213-7
references.pmid: 12676580
references.citation: Clin Cancer Res. 2008 Dec 15;14(24):8302-7
references.pmid: 19088048
references.citation: J Med Chem. 2012 Sep 13;55(17):7786-95
references.pmid: 22938030
references.citation: J Med Chem. 2012 Oct 25;55(20):8603-14
references.pmid: 23006041