title: 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.
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.
authors: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, I-35131 Padova, Italy.
authors: Giuseppe
authors: G
authors: Deganutti
authors: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, I-35131 Padova, Italy.
authors: Alberto
authors: A
authors: Cuzzolin
authors: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, I-35131 Padova, Italy.
authors: Antonella
authors: A
authors: Ciancetta
authors: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, I-35131 Padova, Italy. Electronic address: stefano.moro@unipd.it.
authors: Stefano
authors: S
authors: Moro
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site; D000634:Aminoquinolines / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D043684:Receptor, Adenosine A3 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D007093:Imidazoles; C511637:N-(3,4-dichlorophenyl)-2-cyclohexyl-1H-imidazo(4,5-c)quinolin-4-amine; D043684:Receptor, Adenosine A3; D000241:Adenosine
keywords: Allosteric modulators; G protein-coupled receptors; Human A(3) adenosine receptor antagonists; Supervised Molecular Dynamics