1,2,5-Thiadiazolidin-3-one 1,1 dioxide: a powerful scaffold for probing the S' subsites of (chymo)trypsin-like serine proteases
Groutas, William C. Epp, Jeffrey B. Kuang, Rongze Ruan, Sumei Chong, Lee S. Venkataraman, Radhika Tu, Juan He, Shu Yu, Hongyi Fu, Qingfong
Groutas, William C.
Epp, Jeffrey B.
Kuang, Rongze
Ruan, Sumei
Chong, Lee S.
Venkataraman, Radhika
Tu, Juan
He, Shu
Yu, Hongyi
Fu, Qingfong
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2001-01-01
Type
Article
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Keywords
Research Support, Non-U.S. Gov't,Research Support, U.S. Gov't, P.H.S.
Subjects (LCSH)
Citation
Archives of biochemistry and biophysics. 2001 Jan 1; 385(1): 162-9.
Abstract
The 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I) embodies a motif that allows it to dock to the active site of (chymo)trypsin-like proteases in a predictable and substrate-like fashion. Consequently, inhibitors derived from this heterocyclic scaffold interact with both the S and S' subsites of an enzyme. Exploitation of binding interactions with both the S and S' subsites of a target enzyme may lead to compounds with greatly enhanced enzyme selectivity and inhibitory potency. This preliminary report describes the use of a series of compounds having the heterocyclic scaffold linked to various amino acids to probe the S' subsites of human leukocyte elastase (HLE), proteinase 3 (PR 3), and cathepsin G (Cat G). For comparative purposes, a series of compounds derived from a related scaffold, isothiazolidin-3-one 1,1 dioxide (II), was also generated. Several of the compounds were found to be highly potent and selective time-dependent inhibitors of HLE, PR 3, and Cat G.
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Elsevier
Journal
Archives of Biochemistry and Biophysics
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NLM
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ISSN
0003-9861