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pH‐Dependent Binding Modes Observed in Trypsin Crystals: Lessons for Structure‐Based Drug Design
Author(s) -
Stubbs Milton T.,
Reyda Sabine,
Dullweber Frank,
Möller Maren,
Klebe Gerhard,
Dorsch Dieter,
Mederski Werner W. K. R.,
Wurziger Hanns
Publication year - 2002
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/1439-7633(20020301)3:2/3<246::aid-cbic246>3.0.co;2-#
Subject(s) - trypsin , drug , chemistry , crystallography , stereochemistry , combinatorial chemistry , biophysics , biochemistry , pharmacology , medicine , enzyme , biology
Drug lead compound identification increasingly uses high‐throughput screening in conjunction with computational methods. Hits found in this way are generally of low affinity (typically about 10 −5 M ) and require further development. Such low affinity can result in significant changes in binding mode upon change of experimental conditions: at pH 7, the Factor Xa inhibitor 1 (see picture) binds in the specificity pocket of trypsin through its pyridinyl group (yellow); at pH 8, the same pocket is occupied by the chloronaphthyl moiety (magenta), with a significant reorganization of the ligand binding site (circled).