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Computational approach to site‐directed ligand discovery
Author(s) -
Tóth Gergely,
Mukhyala Kiran,
Wells James A.
Publication year - 2007
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21402
Subject(s) - tethering , binding site , chemistry , conformational change , ligand (biochemistry) , biophysics , small molecule , plasma protein binding , computational biology , receptor , stereochemistry , biochemistry , biology , microbiology and biotechnology
A computational approach, Systematic Conformational Search & Induced Fit (SCI&FI), to site‐directed ligand discovery (Tethering®) is presented. SCI&FI has the ability to predict the binding site, binding mode, and bound dynamics of small molecule fragments covalently tethered to a protein. The SCI&FI method was engineered with the ability to model induced fit conformational changes of the protein because of the binding of the tether. SCI&FI generates comprehensive picture of the binding preferences of the tether to the protein by elucidating potential binding sites of the tether and by describing regions of receptor space capable of conformational change because of the binding of the tether. The SCI&FI method provides a complementary approach to experimental tethering. Initial validation of the SCI&FI method is reported by predicting the 3D structure of two Interleukin‐2 and an Interleukin‐4 tethered‐protein systems. Proteins 2007. © 2007 Wiley‐Liss, Inc.