Glycosidase inhibition: An assessment of the binding of 18 putative transition-state mimics

被引:113
作者
Gloster, Tracey M.
Meloncelli, Peter
Stick, Robert V.
Zechel, David
Vasella, Andrea
Davies, Gideon J. [1 ]
机构
[1] Univ York, York Struct Biol Lab, Dept Chem, York YO10 5YW, N Yorkshire, England
[2] Univ Western Australia, Sch Biomed Biomol & Chem Sci M313, Crawley, WA 6009, Australia
[3] Queens Univ, Dept Chem, Kingston, ON K7L 3N6, Canada
[4] ETH, Organ Chem Lab, HCI H317, CH-8093 Zurich, Switzerland
关键词
D O I
10.1021/ja066961g
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The inhibition of glycoside hydrolases, through transition-state mimicry, is important both as a probe of enzyme mechanism and in the continuing quest for new drugs, notably in the treatment of cancer, HIV, influenza, and diabetes. The high affinity with which these enzymes are known to bind the transition state provides a framework upon which to design potent inhibitors. Recent work [for example, BUlow, A. et al. J. Am. Chem. Soc. 2000, 122, 8567-8568; Zechel, D. L. et al. J. Am. Chem. Soc. 2003, 125, 14313-14323] has revealed quite confusing and counter-intuitive patterns of inhibition for a number of glycosidase inhibitors. Here we describe a synergistic approach for analysis of inhibitors with a single enzyme 'model system', the Thermotoga maritima family 1 beta-glucosidase, TmGH1. The pH dependence of enzyme activity and inhibition has been determined, structures of inhibitor complexes have been solved by X-ray crystallography, with data up to 1.65 A resolution, and isothermal titration calorimetry was used to establish the thermodynamic signature. This has allowed the characterization of 18 compounds, all putative transition-state mimics, in order to build an 'inhibition profile' that provides an insight into what governs binding. In contrast to our preconceptions, there is little correlation of inhibitor chemistry with the calorimetric dissection of thermodynamics. The ensemble of inhibitors shows strong enthalpy-entropy compensation, and the random distribution of similar inhibitors across the plot of Delta H degrees(a) vs T Delta S degrees(a) likely reflects the enormous contribution of solvation and desolvation effects on ligand binding.
引用
收藏
页码:2345 / 2354
页数:10
相关论文
共 94 条
[41]   Three-dimensional structure of the barley β-D-glucan glucohydrolase in complex with a transition state mimic [J].
Hrmova, M ;
De Gori, R ;
Smith, BJ ;
Vasella, A ;
Varghese, JN ;
Fincher, GB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (06) :4970-4980
[42]  
Jensen HH, 2001, ANGEW CHEM INT EDIT, V40, P3447, DOI 10.1002/1521-3773(20010917)40:18<3447::AID-ANIE3447>3.0.CO
[43]  
2-8
[44]  
JESPERSEN TM, 1994, TETRAHEDRON, V50, P13449
[45]   ISOFAGOMINE, A POTENT, NEW GLYCOSIDASE INHIBITOR [J].
JESPERSEN, TM ;
DONG, WL ;
SIERKS, MR ;
SKRYDSTRUP, T ;
LUNDT, I ;
BOLS, M .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION IN ENGLISH, 1994, 33 (17) :1778-1779
[46]   INTRINSIC PKA-VALUES OF FUNCTIONAL-GROUPS IN ENZYMES - IMPROPER DEDUCTIONS FROM PH-DEPENDENCE OF STEADY-STATE PARAMETERS [J].
KNOWLES, JR .
CRC CRITICAL REVIEWS IN BIOCHEMISTRY, 1976, 4 (02) :165-173
[47]  
Krishnamurthy V. M., 2006, J. Am. Chem. Soc, V128, P5802
[48]  
Leatherbarrow R.J., 2001, GRAFIT VERSION 5
[49]   Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase [J].
Lee, JE ;
Singh, V ;
Evans, GB ;
Tyler, PC ;
Furneaux, RH ;
Cornell, KA ;
Riscoe, MK ;
Schramm, VL ;
Howell, PL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (18) :18274-18282
[50]   GLYCOSIDE HYDROLASES - MECHANISTIC INFORMATION FROM STUDIES WITH REVERSIBLE AND IRREVERSIBLE INHIBITORS [J].
LEGLER, G .
ADVANCES IN CARBOHYDRATE CHEMISTRY AND BIOCHEMISTRY, 1990, 48 :319-384