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In‐crystal chemical ligation for lead compound generation
Author(s) -
Yamane Junji,
Ohyabu Naoki,
Yao Min,
Takemoto Hiroshi,
Tanaka Isao
Publication year - 2010
Publication title -
journal of applied crystallography
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.429
H-Index - 162
ISSN - 1600-5767
DOI - 10.1107/s0021889810037222
Subject(s) - molecule , bifunctional , native chemical ligation , chemistry , benzamidine , combinatorial chemistry , chemical ligation , crystallography , crystal (programming language) , nanotechnology , materials science , cysteine , computer science , amino acid , organic chemistry , catalysis , biochemistry , enzyme , programming language
A new fragment‐based growth strategy for lead compound generation is proposed, which is based on in situ chemical ligation and is operable in X‐ray‐based fragment screening format. The method involves two classes of bifunctional molecules, referred to as anchor molecules and tuning molecules. The anchor molecules are designed to form stable complexes with target proteins and to connect with the tuning molecules. The procedure begins with the introduction of the anchor molecule into the target protein, to which the tuning molecule is linked in the crystal. Proof‐of‐concept experiments using trypsin crystals charged with para ‐aldehyde benzamidine showed that the crystals acted as a platform to select self‐assembled ligation products. Furthermore, time‐resolved crystallography allowed identification of the reaction field and direct visualization of the reaction pathway. The ability to rapidly gain an understanding of the relations between a set of chemical modifications and their interactions with target proteins would accelerate the hit‐to‐lead process. A potential crystallographic growth strategy via the self‐assembly technique and its biological implications are discussed.