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Theoretical studies on the conformational change of adenosine kinase induced by inhibitors
Author(s) -
Dong Lihua,
Shi Junyou,
Wang Jinhu,
Liu Yongjun
Publication year - 2010
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.22939
Subject(s) - chemistry , docking (animal) , adenosine , adenosine kinase , stereochemistry , binding site , conformational change , molecular dynamics , nucleoside , binding domain , phosphorylation , biophysics , biochemistry , computational chemistry , biology , medicine , nursing , adenosine deaminase
Adenosine kinase (AK) is a two‐domain protein that catalyzes the phosphorylation of adenosine to adenosine monophosphate. Inhibitors of AK could increase adenosine to levels that activate nearby adenosine receptors and produce a wide variety of therapeutically beneficial activities. To get insight into the interaction mechanism between inhibitors and AK, we chose two kinds of novel inhibitors, alkynylpyrimidine inhibitor (APy) and aryl‐nucleoside inhibitor (AN), and used docking and molecular dynamics simulation methods to study the conformational changes of human AK on binding inhibitors. The calculation results revealed that both APy and AN could induce conformational changes of AK and stabilize AK at different semiopen conformations. On binding APy, the small lid‐domain rotated 14°, and the binding pocket rearranged after MD simulation. But in AK‐AN complex, the rotation of small domain is 22°, and the sugar ring of AN is mobile in the binding pocket. Further docking calculations on APy analogues indicate that the semiopen conformation could well explain the SAR of AK inhibitors. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011