Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A1 Receptor

Journal Article · · Scientific Reports
 [1];  [1];  [2];  [2];  [2]
  1. Univ. of Kansas, Lawrence, KS (United States)
  2. Monash Univ., Parkville (Australia)
+ Show Author Affiliations

Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Organization:
USDOE Office of Science (SC)
OSTI ID:
1543783
Journal Information:
Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 8; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

References (121)

Synthesis of 2-Amino-3-heteroaroylthiophenes and Evaluation of Their Activity as Potential Allosteric Enhancers at the Human A1 Receptor. journal March 2005
The Amber biomolecular simulation programs journal January 2005
On searching in, sampling of, and dynamically moving through conformational space of biomolecular systems: A review journal January 2007
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields journal January 2009
Transition Path Sampling and Other Advanced Simulation Techniques for Rare Events book January 2009
The effect of acidic pH on the adsorption and lytic activity of the peptides Polybia-MP1 and its histidine-containing analog in anionic lipid membrane: a biophysical study by molecular dynamics and spectroscopy journal April 2021
CHARMM additive and polarizable force fields for biophysics and computer-aided drug design journal May 2015
The role of the second and third extracellular loops of the adenosine A1 receptor in activation and allosteric modulation journal July 2012
Enhanced sampling techniques in biomolecular simulations journal November 2015
3- and 6-Substituted 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines as A1 adenosine receptor allosteric modulators and antagonists journal October 2009
The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A1 adenosine receptor journal June 2011
Allosteric modulation of A1-adenosine receptor: a review journal June 2013
Ligand Entry and Exit Pathways in the β2-Adrenergic Receptor journal October 2009
Structures of Human A 1 and A 2A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity journal August 2017
Allosteric modulators of G-protein-coupled receptors journal October 2003
An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands journal May 2017
Gaussian Accelerated Molecular Dynamics in NAMD journal December 2016
Mechanistic Insights into the Allosteric Modulation of Opioid Receptors by Sodium Ions journal July 2014
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data journal June 2013
Improved Reweighting of Accelerated Molecular Dynamics Simulations for Free Energy Calculation journal May 2014
Chromophore Channeling in the G-Protein Coupled Receptor Rhodopsin journal June 2007
2-Amino-3-benzoylthiophene Allosteric Enhancers of A 1 Adenosine Agonist Binding:  New 3, 4-, and 5-Modifications journal May 2003
Allosteric Modulators of the Adenosine A 1 Receptor: Synthesis and Pharmacological Evaluation of 4-Substituted 2-Amino-3-benzoylthiophenes journal July 2009
Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation journal May 2011
Structure and dynamics of the M3 muscarinic acetylcholine receptor journal February 2012
Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs journal October 2013
Activation and allosteric modulation of a muscarinic acetylcholine receptor journal November 2013
Trends in GPCR drug discovery: new agents, targets and indications journal October 2017
Adenosine receptors as therapeutic targets journal March 2006
Molecular dynamics simulations of biomolecules journal September 2002
Stepwise gating of the Sec61 protein-conducting channel by Sec63 and Sec62 journal January 2021
Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules journal June 2004
Sampling of slow diffusive conformational transitions with accelerated molecular dynamics journal October 2007
A statistical analysis of the precision of reweighting-based simulations journal July 2008
Pathway and mechanism of drug binding to G-protein-coupled receptors journal July 2011
Graded activation and free energy landscapes of a muscarinic G-protein–coupled receptor journal October 2016
CRISPR-Cas9 conformational activation as elucidated from enhanced molecular simulations journal June 2017
Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor journal March 2018
Escaping free-energy minima journal September 2002
Thermodynamics and kinetics simulations of multi-time-scale processes for complex systems journal April 2008
Unconstrained enhanced sampling for free energy calculations of biomolecules: a review journal July 2016
Allosteric Adenosine Receptor Modulation Reduces Hypersensitivity Following Peripheral Inflammation by a Central Mechanism journal February 2003
Molecular Basis of Ligand Dissociation from the Adenosine A 2A Receptor journal February 2016
Role of the Second Extracellular Loop of the Adenosine A 1 Receptor on Allosteric Modulator Binding, Signaling, and Cooperativity journal September 2016
International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update journal February 2011
The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist journal November 2008
Structure of an Agonist-Bound Human A2A Adenosine Receptor journal March 2011
Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors journal September 2011
Allosteric Enhancers of A1 Adenosine Receptors: State of the Art and New Horizons for Drug Development journal October 2010
Allosteric Enhancers for A1 Adenosine Receptor journal June 2007
Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration text January 2014
Scalable molecular dynamics with NAMD journal January 2005
The Amber biomolecular simulation programs journal January 2005
On searching in, sampling of, and dynamically moving through conformational space of biomolecular systems: A review journal January 2007
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields journal January 2009
VMD: Visual molecular dynamics journal February 1996
The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A1 adenosine receptor journal June 2011
Synthesis and biological effects of a new series of 2-amino-3-benzoylthiophenes as allosteric enhancers of A1-adenosine receptor journal September 2000
[19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors book January 1995
Allosteric modulators of G-protein-coupled receptors journal October 2003
CHARMM additive and polarizable force fields for biophysics and computer-aided drug design journal May 2015
Allosteric modulation of adenosine receptors journal May 2011
The role of the second and third extracellular loops of the adenosine A1 receptor in activation and allosteric modulation journal July 2012
Enhanced sampling techniques in biomolecular simulations journal November 2015
3- and 6-Substituted 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines as A1 adenosine receptor allosteric modulators and antagonists journal October 2009
Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity journal February 2017
Allosteric modulation of A1-adenosine receptor: a review journal June 2013
Synthesis of 2-amino-3-heteroaroylthiophenes and evaluation of their activity as potential allosteric enhancers at the human A1 receptor journal October 2004
Ligand Entry and Exit Pathways in the β2-Adrenergic Receptor journal October 2009
Computational techniques for efficient conformational sampling of proteins journal April 2008
G-protein coupled receptors: advances in simulation and drug discovery journal December 2016
Structures of Human A 1 and A 2A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity journal August 2017
Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor journal July 2015
Mechanistic Insights into the Allosteric Modulation of Opioid Receptors by Sodium Ions journal July 2014
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data journal June 2013
Synthesis and Characterization of Novel 2-Amino-3-benzoylthiophene Derivatives as Biased Allosteric Agonists and Modulators of the Adenosine A 1 Receptor journal February 2012
Allosteric Modulators of the Adenosine A 1 Receptor: Synthesis and Pharmacological Evaluation of 4-Substituted 2-Amino-3-benzoylthiophenes journal July 2009
An Efficient Metadynamics-Based Protocol To Model the Binding Affinity and the Transition State Ensemble of G-Protein-Coupled Receptor Ligands journal May 2017
Gaussian Accelerated Molecular Dynamics: Unconstrained Enhanced Sampling and Free Energy Calculation journal July 2015
Gaussian Accelerated Molecular Dynamics in NAMD journal December 2016
Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug–Target Interactions journal February 2018
Improved Reweighting of Accelerated Molecular Dynamics Simulations for Free Energy Calculation journal May 2014
Chromophore Channeling in the G-Protein Coupled Receptor Rhodopsin journal June 2007
2-Amino-3-aroyl-4,5-alkylthiophenes:  Agonist Allosteric Enhancers at Human A 1 Adenosine Receptors journal January 2002
2-Amino-3-benzoylthiophene Allosteric Enhancers of A 1 Adenosine Agonist Binding:  New 3, 4-, and 5-Modifications journal May 2003
Synthesis and Biological Evaluation of Novel Allosteric Enhancers of the A 1 Adenosine Receptor Based on 2-Amino-3-(4′-Chlorobenzoyl)-4-Substituted-5-Arylethynyl Thiophene journal September 2014
Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs journal October 2013
Molecular dynamics simulations of biomolecules journal September 2002
Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation journal May 2011
Structure and dynamics of the M3 muscarinic acetylcholine receptor journal February 2012
Activation and allosteric modulation of a muscarinic acetylcholine receptor journal November 2013
Trends in GPCR drug discovery: new agents, targets and indications journal October 2017
Adenosine receptors as therapeutic targets journal March 2006
Structure of the adenosine-bound human adenosine A1 receptor–Gi complex journal June 2018
Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules journal June 2004
Sampling of slow diffusive conformational transitions with accelerated molecular dynamics journal October 2007
A statistical analysis of the precision of reweighting-based simulations journal July 2008
Escaping free-energy minima journal September 2002
Pathway and mechanism of drug binding to G-protein-coupled receptors journal July 2011
Graded activation and free energy landscapes of a muscarinic G-protein–coupled receptor journal October 2016
CRISPR-Cas9 conformational activation as elucidated from enhanced molecular simulations journal June 2017
Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor journal March 2018
Thermodynamics and kinetics simulations of multi-time-scale processes for complex systems journal April 2008
Unconstrained enhanced sampling for free energy calculations of biomolecules: a review journal July 2016
Metadynamics: a method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science journal November 2008
A density based algorithm for discovering clusters with varied density conference January 2014
Allosteric interactions at adenosine A 1 and A 3 receptors: new insights into the role of small molecules and receptor dimerization : Allosterism at adenosine A journal February 2014
Allosteric modulation of adenosine A1 receptor coupling to G-proteins in brain journal May 2005
Allosteric Adenosine Receptor Modulation Reduces Hypersensitivity Following Peripheral Inflammation by a Central Mechanism journal February 2003
A Positive Allosteric Modulator of the Adenosine A 1 Receptor Selectively Inhibits Primary Afferent Synaptic Transmission in a Neuropathic Pain Model journal June 2015
Molecular Basis of Ligand Dissociation from the Adenosine A 2A Receptor journal February 2016
Role of the Second Extracellular Loop of the Adenosine A 1 Receptor on Allosteric Modulator Binding, Signaling, and Cooperativity journal September 2016
International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update journal February 2011
The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist journal November 2008
Structure of an Agonist-Bound Human A2A Adenosine Receptor journal March 2011
Allosteric Modulation of G Protein–Coupled Receptors journal February 2007
AMBER 14, University of California, San Francisco dataset January 2014
Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors journal September 2011
Allosteric Enhancers of A1 Adenosine Receptors: State of the Art and New Horizons for Drug Development journal October 2010
Allosteric Enhancers for A1 Adenosine Receptor journal June 2007
Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration journal December 2013

Cited By (7)

G‐Protein‐Coupled Receptor–Membrane Interactions Depend on the Receptor Activation State journal October 2019
The effect of dimerization on the activation and conformational dynamics of adenosine A 1 receptor journal January 2019
Structure-based design and analysis of SuFEx chemical probes journal January 2020
The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations journal November 2019
Historical and Current Adenosine Receptor Agonists in Preclinical and Clinical Development journal March 2019
The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations text January 2019
The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations text January 2019

Similar Records

Related Subjects

60 APPLIED LIFE SCIENCES
Other Topics
Science & Technology