Structural, kinetic, and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors

Tracey M. Gloster; Shirley Roberts; Giuseppe Perugino; Mose Rossi; Marco Moracci; Narendra Panday; Miroslav Terinek; Andrea Vasella; Gideon J. Davies

doi:10.1021/bi060973x

Structural, kinetic, and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors

Tracey M. Gloster, Shirley Roberts, Giuseppe Perugino, Mose Rossi, Marco Moracci, Narendra Panday, Miroslav Terinek, Andrea Vasella, Gideon J. Davies

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

Abstract

Inhibition of glycosidases has great potential in the quest for highly potent and specific drugs to treat diseases such as diabetes, cancer, and viral infections. One of the most effective ways of designing such compounds is by mimicking the transition state. Here we describe the structural, kinetic, and thermodynamic dissection of binding of two glucoimidazole-derived compounds, which are among the most potent glycosidase inhibitors reported to date, with two family 1 beta-glycosidases. Provocatively, while inclusion of the phenethyl moiety improves binding by a factor of 20-80-fold, this does not appear to result from better noncovalent interactions with the enzyme; instead, improved affinity may be derived from significantly better entropic contributions to binding displayed by the phenethyl-substituted imidazole compound.

Original language	English
Pages (from-to)	11879-11884
Number of pages	6
Journal	Biochemistry
Volume	45
Issue number	39
DOIs	https://doi.org/10.1021/bi060973x
Publication status	Published - 3 Oct 2006

Keywords

TRANSITION-STATE
SUBSTRATE DISTORTION
MOLECULAR GRAPHICS
BETA-GLUCOSIDASES
BINDING
GLUCOHYDROLASE
DISSECTION
DEPENDENCE
SNAPSHOTS
COMPLEX

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/bi060973x

Cite this

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title = "Structural, kinetic, and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors",

abstract = "Inhibition of glycosidases has great potential in the quest for highly potent and specific drugs to treat diseases such as diabetes, cancer, and viral infections. One of the most effective ways of designing such compounds is by mimicking the transition state. Here we describe the structural, kinetic, and thermodynamic dissection of binding of two glucoimidazole-derived compounds, which are among the most potent glycosidase inhibitors reported to date, with two family 1 beta-glycosidases. Provocatively, while inclusion of the phenethyl moiety improves binding by a factor of 20-80-fold, this does not appear to result from better noncovalent interactions with the enzyme; instead, improved affinity may be derived from significantly better entropic contributions to binding displayed by the phenethyl-substituted imidazole compound.",

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author = "Gloster, {Tracey M.} and Shirley Roberts and Giuseppe Perugino and Mose Rossi and Marco Moracci and Narendra Panday and Miroslav Terinek and Andrea Vasella and Davies, {Gideon J.}",

year = "2006",

month = oct,

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doi = "10.1021/bi060973x",

language = "English",

volume = "45",

pages = "11879--11884",

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TY - JOUR

T1 - Structural, kinetic, and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors

AU - Gloster, Tracey M.

AU - Roberts, Shirley

AU - Perugino, Giuseppe

AU - Rossi, Mose

AU - Moracci, Marco

AU - Panday, Narendra

AU - Terinek, Miroslav

AU - Vasella, Andrea

AU - Davies, Gideon J.

PY - 2006/10/3

Y1 - 2006/10/3

N2 - Inhibition of glycosidases has great potential in the quest for highly potent and specific drugs to treat diseases such as diabetes, cancer, and viral infections. One of the most effective ways of designing such compounds is by mimicking the transition state. Here we describe the structural, kinetic, and thermodynamic dissection of binding of two glucoimidazole-derived compounds, which are among the most potent glycosidase inhibitors reported to date, with two family 1 beta-glycosidases. Provocatively, while inclusion of the phenethyl moiety improves binding by a factor of 20-80-fold, this does not appear to result from better noncovalent interactions with the enzyme; instead, improved affinity may be derived from significantly better entropic contributions to binding displayed by the phenethyl-substituted imidazole compound.

AB - Inhibition of glycosidases has great potential in the quest for highly potent and specific drugs to treat diseases such as diabetes, cancer, and viral infections. One of the most effective ways of designing such compounds is by mimicking the transition state. Here we describe the structural, kinetic, and thermodynamic dissection of binding of two glucoimidazole-derived compounds, which are among the most potent glycosidase inhibitors reported to date, with two family 1 beta-glycosidases. Provocatively, while inclusion of the phenethyl moiety improves binding by a factor of 20-80-fold, this does not appear to result from better noncovalent interactions with the enzyme; instead, improved affinity may be derived from significantly better entropic contributions to binding displayed by the phenethyl-substituted imidazole compound.

KW - TRANSITION-STATE

KW - SUBSTRATE DISTORTION

KW - MOLECULAR GRAPHICS

KW - BETA-GLUCOSIDASES

KW - BINDING

KW - GLUCOHYDROLASE

KW - DISSECTION

KW - DEPENDENCE

KW - SNAPSHOTS

KW - COMPLEX

U2 - 10.1021/bi060973x

DO - 10.1021/bi060973x

M3 - Article

SN - 0006-2960

VL - 45

SP - 11879

EP - 11884

JO - Biochemistry

JF - Biochemistry

IS - 39

ER -

Structural, kinetic, and thermodynamic analysis of glucoimidazole-derived glycosidase inhibitors

Abstract

Keywords

UN SDGs

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