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Bioorg Med Chem. 2015 Jul 15;23(14):4065-71. doi: 10.1016/j.bmc.2015.03.039. Epub 2015 Mar 20.

Understanding allosteric interactions in G protein-coupled receptors using Supervised Molecular Dynamics: A prototype study analysing the human A3 adenosine receptor positive allosteric modulator LUF6000.

Author information

  • 1Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Universit√† di Padova, via Marzolo 5, I-35131 Padova, Italy.
  • 2Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Universit√† di Padova, via Marzolo 5, I-35131 Padova, Italy. Electronic address: stefano.moro@unipd.it.

Abstract

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 A3 receptor (hA3 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.

KEYWORDS:

Allosteric modulators; G protein-coupled receptors; Human A(3) adenosine receptor antagonists; Supervised Molecular Dynamics

PMID:
25868747
DOI:
10.1016/j.bmc.2015.03.039
[PubMed - indexed for MEDLINE]
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