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Comparative Analysis of Putative Agonist‐Binding Modes in the Human A 1 Adenosine Receptor
Author(s) -
GutiérrezdeTerán Hugo,
Pastor Manuel,
Centeno Nuria B.,
Åqvist Johan,
Sanz Ferran
Publication year - 2004
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/cbic.200300817
Subject(s) - autodock , adenosine receptor , agonist , adenosine , ccpa , adenosine a2b receptor , binding site , chemistry , docking (animal) , adenosine a1 receptor , stereochemistry , receptor , biochemistry , biophysics , biology , in silico , medicine , nursing , gene
A recent study reported a model of the human A 1 adenosine receptor and its agonist binding site, proposing two putative binding modes in the same binding site for the natural agonist, adenosine. The present work investigates the flexibility of this binding site by exhaustive exploration with the natural agonist and with three other adenosine derivatives: N 6‐cyclopentyladenosine (CPA), 2‐chloro‐ N 6‐cyclopentyladenosine (CCPA), and 5′‐ N ‐ethylcarboxamidoadenosine (NECA). Our aim was to find a common binding mode for agonists that would explain the role in the binding process of the different substitutions allowed at the 2, N 6, and 5′ positions of adenosine. This problem was addressed through docking simulations, molecular dynamics studies, and estimations of the ligand‐binding free energy with both the AUTODOCK scoring function and the linear interaction energy (LIE) approach. The results point to a single receptor‐binding position that explains the effects of the different chemical modifications on the adenosine derivatives considered here.