The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors - characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors

doi:10.1039/c2md20268a

	The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors - characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors
	Gossas, Thomas 2; Nordstrom, Helena 2; Xu, Ming-Hua1 ; Sun, Zhi-Hua 4; Lin, Guo-Qiang 4; Wallberg, Hans 3; Danielson, U. Helena 2
刊名	MEDCHEMCOMM
	2013-02
卷号	4 期号:2 页码:432-442
ISSN号	2040-2503
DOI	10.1039/c2md20268a
文献子类	Article
英文摘要	The kinetic characteristics of hydroxamate-based inhibitors of matrix metalloproteinase (MMP)-12 were explored using an SPR biosensor-based assay and enzyme inhibition analysis. These high-affinity inhibitors were shown to dissociate very slowly from the enzyme-inhibitor complex while a carboxylate analogue had a much faster dissociation rate, verifying the importance of the hydroxamate group for the slow dissociation. Progress curve enzyme inhibition analysis confirmed that the hydroxamate compounds but not the carboxylate compound acted as time-dependent inhibitors. The slow dissociation excluded steady-state estimation of IC50-values and K-i values but also made K-i values from progress curve analysis unreliable. Although a full characterization of the inhibitors using biosensor analysis was limited by slow dissociation, it provided kinetic and mechanistic information of relevance for MMP drug discovery and avoided some pitfalls of conventional enzyme inhibition assays.
资助项目	Swedish Agency for Innovation Systems (VINNOVA)[00000000] ; Swedish Research Council (VR)[00000000]
WOS关键词	MACROPHAGE ELASTASE MMP-12 ; CANCER-THERAPY ; BINDING INHIBITORS ; CRYSTAL-STRUCTURE ; HIV-1 PROTEASE ; DESIGN ; POTENT ; MMPS ; TECHNOLOGY ; DISCOVERY
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000314311600020
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277751]
专题	药物化学研究室
通讯作者	Danielson, U. Helena
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Uppsala Univ, Dept Chem BMC, SE-75123 Uppsala, Sweden; 3.Medivir AB, S-14122 Huddinge, Sweden 4.Chinese Acad Sci, Shanghai Inst Organ Chem, Shanghai 200032, Peoples R China;
推荐引用方式 GB/T 7714	Gossas, Thomas,Nordstrom, Helena,Xu, Ming-Hua,et al. The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors - characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors[J]. MEDCHEMCOMM,2013,4(2):432-442.
APA	Gossas, Thomas.,Nordstrom, Helena.,Xu, Ming-Hua.,Sun, Zhi-Hua.,Lin, Guo-Qiang.,...&Danielson, U. Helena.(2013).The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors - characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors.MEDCHEMCOMM,4(2),432-442.
MLA	Gossas, Thomas,et al."The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors - characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors".MEDCHEMCOMM 4.2(2013):432-442.