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X‐ray Crystal Structure of a Bisubstrate Inhibitor Bound to the Enzyme Catechol‐ O ‐methyltransferase: A Dramatic Effect of Inhibitor Preorganization on Binding Affinity
Author(s) -
Lerner Christian,
Ruf Armin,
Gramlich Volker,
Masjost Birgit,
Zürcher Gerhard,
JakobRoetne Roland,
Borroni Edilio,
Diederich François
Publication year - 2001
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/1521-3773(20011105)40:21<4040::aid-anie4040>3.0.co;2-c
Subject(s) - catechol o methyl transferase , chemistry , enzyme , enzyme inhibitor , stereochemistry , ic50 , catechol , biochemistry , in vitro , allele , gene
With an IC 50 value of 9 n M , 1 is the most potent known disubstrate inhibitor for catechol‐ O ‐methyltransferase (COMT). Inhibition of COMT is of significant interest in the therapy of Parkinsonapos;s disease since it ensures that a larger percentage of orally administered L ‐dopa reaches—in the form of dopamine—its target in the brain. The X‐ray crystal structure of a complex formed by COMT and 1 has been solved at 2.6‐Å resolution.