Virtual screening and biophysical studies lead to HSP90 inhibitors

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• 作者：Renjie Huang ; Daniel M. Ayine-Tora ; M. Nasri Muhammad Rosdi ; Yu Li ; Jó ; hannes Reynisson ; ^{j.reynisson@auckland.ac.nz} ; Ivanhoe K.H. Leung ; ^{i.leung@auckland.ac.nz}
• 关键词：17-AAG ; 17-allylamino-17-demethoxygeldanamycin ; 17-DMAG ; 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) ; ADP ; adenosine diphosphate ; AMPPCP ; 5&prime ; -adenylylmethylenediphosphonate ; ASP ; Astex statistical potential ; ATP ; adenosine triphosphate ; CS ; ChemScore ; GS ; GoldScore ; HB ; hydrogen bonding ; HSP90 ; heat shock protein 90 ; HSQC ; heteronuclear single quantum correlation ; KD ; binding affinity ; ND ; N-domain ; NMR ; nuclear magnetic resonance ; NOE ; nuclear Overhauser effect ; Tm ; pro
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：27
• 期：2
• 页码：277-281
• 全文大小：1125 K
• 卷排序：27

文摘

Heat shock protein 90 (HSP90) is a molecular chaperone that plays important functional roles in cells. The chaperone activity of HSP90 is regulated by the hydrolysis of ATP at the protein’s N-terminal domain. HSP90, in particular the N-terminal domain, is a current inhibition target for therapeutic treatments of cancers. This paper describes an application of virtual screening, thermal shift assaying and protein NMR spectroscopy leading to the discovery of HSP90 inhibitors that contain the resorcinol structure. The resorcinol scaffold can be found in a class of HSP90 inhibitors that are currently undergoing clinical trials. The proved success of the resorcinol moiety in HSP90 inhibitors validates this combined virtual screen and biophysical technique approach, which may be applied for future inhibitor discovery work for HSP90 as well as other targets.