Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 14, Pages 4065-4071Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.03.039
Keywords
G protein-coupled receptors; Allosteric modulators; Human A(3) adenosine receptor antagonists; Supervised Molecular Dynamics
Funding
- University of Padova, Italy
- Italian Ministry for University and Research, Rome, Italy (MIUR) [200834TC4L_002]
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The search for G protein-coupled receptors (GPCRs) allosteric modulators represents an active research field in medicinal chemistry. Allosteric modulators usually exert their activity only in the presence of the orthosteric ligand by binding to protein sites topographically different from the orthosteric cleft. They therefore offer potentially therapeutic advantages by selectively influencing tissue responses only when the endogenous agonist is present. The prediction of putative allosteric site location, however, is a challenging task. In facts, they are usually located in regions showing more structural variation among the family members. In the present work, we applied the recently developed Supervised Molecular Dynamics (SuMD) methodology to interpret at the molecular level the positive allosteric modulation mediated by LUF6000 toward the human adenosine A(3) receptor (hA(3) AR). Our data suggest at least two possible mechanisms to explain the experimental data available. This study represent, to the best of our knowledge, the first case reported of an allosteric recognition mechanism depicted by means of molecular dynamics simulations. (C) 2015 Elsevier Ltd. All rights reserved.
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