Molecular Dynamics Simulations of Adenosine Receptors: Advances, Applications and Trends

Author(s): Nizar A. Al-Shar'i*, Qosay A. Al-Balas.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 7 , 2019


Abstract:

Adenosine receptors (ARs) are transmembrane proteins that belong to the G protein-coupled receptors (GPCRs) superfamily and mediate the biological functions of adenosine. To date, four AR subtypes are known, namely A1, A2A, A2B and A3 that exhibit different signaling pathways, tissue localization, and mechanisms of activation. Moreover, the widespread ARs and their implication in numerous physiological and pathophysiological conditions had made them pivotal therapeutic targets for developing clinically effective agents.

The crystallographic success in identifying the 3D crystal structures of A2A and A1 ARs has dramatically enriched our understanding of their structural and functional properties such as ligand binding and signal transduction. This, in turn, has provided a structural basis for a larger contribution of computational methods, particularly molecular dynamics (MD) simulations, toward further investigation of their molecular properties and designing bioactive ligands with therapeutic potential. MD simulation has been proved to be an invaluable tool in investigating ARs and providing answers to some critical questions. For example, MD has been applied in studying ARs in terms of ligand-receptor interactions, molecular recognition, allosteric modulations, dimerization, and mechanisms of activation, collectively aiding in the design of subtype selective ligands.

In this review, we focused on the advances and different applications of MD simulations utilized to study the structural and functional aspects of ARs that can foster the structure-based design of drug candidates. In addition, relevant literature was briefly discussed which establishes a starting point for future advances in the field of drug discovery to this pivotal group of drug targets.

Keywords: Adenosine receptors, molecular dynamics simulation, GPCRs, drug design, allosteric modulation, molecular switches.

[1]
Ballesteros JA, Weinstein H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods in Neurosciences 1995; pp. 366-428.
[2]
Kolakowski LF Jr. GCRDb: A G-protein-coupled receptor database. Receptors Channels 1994; 2(1): 1-7.
[3]
Isberg V, Vroling B, van der Kant R, Li K, Vriend G, Gloriam D. GPCRDB: An information system for G protein-coupled receptors. Nucleic Acids Res 2014; 42(Database issue): D422-5.
[4]
Isberg V, de Graaf C, Bortolato A, et al. Generic GPCR residue numbers - aligning topology maps while minding the gaps. Trends Pharmacol Sci 2015; 36(1): 22-31.
[5]
Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001; 53(4): 527-52.
[6]
Cunha RA. Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem Int 2001; 38(2): 107-25.
[7]
Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998; 50(3): 413-92.
[8]
Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev 2011; 63(1): 1-34.
[9]
Lasley RD. Adenosine receptors and membrane microdomains. Biochim Biophys Acta 2011; 1808(5): 1284-9.
[10]
Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V. Adenosine receptors: expression, function and regulation. Int J Mol Sci 2014; 15(2): 2024-52.
[11]
Da Silva RS. Caffeine. Reproduct Develop Toxicol 2011; pp. 355-64.
[12]
Wei CJ, Li W, Chen J-F. Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. Biochim Biophys Acta 2011; 1808(5): 1358-79.
[13]
Chen J-F, Eltzschig HK, Fredholm BB. Adenosine receptors as drug targets--what are the challenges? Nat Rev Drug Discov 2013; 12(4): 265-86.
[14]
Jacobson KA, Gao Z-G. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 2006; 5(3): 247-64.
[15]
Sérgio JM Jr, Murilo LC, Adair RSS. Pharmacology of adenosine receptors and their signaling role in immunity and inflammation, pharmacology and therapeutics. Pharmacol Ther 2014.
[16]
Johansson SM, Yang JN, Lindgren E, Fredholm BB. Eliminating the antilipolytic adenosine A1 receptor does not lead to compensatory changes in the antilipolytic actions of PGE2 and nicotinic acid. Acta Physiol (Oxf) 2007; 190(1): 87-96.
[17]
Sun D, Samuelson LC, Yang T, et al. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc Natl Acad Sci USA 2001; 98(17): 9983-8.
[18]
Liu XL, Zhou R, Pan QQ, et al. Genetic inactivation of the adenosine A2A receptor attenuates pathologic but not developmental angiogenesis in the mouse retina. Invest Ophthalmol Vis Sci 2010; 51(12): 6625-32.
[19]
Headrick JP, Peart JN, Reichelt ME, Haseler LJ. Adenosine and its receptors in the heart: regulation, retaliation and adaptation. Biochim Biophys Acta 2011; 1808(5): 1413-28.
[20]
Headrick JP, Lasley RD. Adenosine receptors and reperfusion injury of the heart. Handb Exp Pharmacol 2009; 193(193): 189-214.
[21]
Johnston-Cox HA, Koupenova M, Ravid K. A2 adenosine receptors and vascular pathologies. Arterioscler Thromb Vasc Biol 2012; 32(4): 870-8.
[22]
Fishman P, Bar-Yehuda S, Synowitz M, et al. Adenosine receptors and cancer. Handb Exp Pharmacol 2009; 193(193): 399-441.
[23]
Eltzschig HK, Sitkovsky MV, Robson SC. Purinergic signaling during inflammation. N Engl J Med 2012; 367(24): 2322-33.
[24]
Haskó G, Linden J, Cronstein B, Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 2008; 7(9): 759-70.
[25]
Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA. Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 2011; 1808(5): 1380-99.
[26]
Varani K, Padovan M, Govoni M, Vincenzi F, Trotta F, Borea PA. The role of adenosine receptors in rheumatoid arthritis. Autoimmun Rev 2010; 10(2): 61-4.
[27]
Cheong SL, Federico S, Venkatesan G, et al. The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches. Med Res Rev 2013; 33(2): 235-335.
[28]
Müller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 2011; 1808(5): 1290-308.
[29]
Geldenhuys WJ, Hanif A, Yun J, Nayeem MA. Exploring Adenosine Receptor Ligands: Potential Role in the Treatment of Cardiovascular Diseases. Molecules 2017; 22(6): 917.
[30]
Rizzolio F, La Montagna R, Tuccinardi T, Russo G, Caputi M, Giordano A. Adenosine receptor ligands in clinical trials. Curr Top Med Chem 2010; 10(10): 1036-45.
[31]
Allard D, Turcotte M, Stagg J. Targeting A2 adenosine receptors in cancer. Immunol Cell Biol 2017; 95(4): 333-9.
[32]
Fishman P, Bar-Yehuda S, Ardon E, et al. Targeting the A3 adenosine receptor for cancer therapy: inhibition of prostate carcinoma cell growth by A3AR agonist. Anticancer Res 2003; 23(3A): 2077-83.
[33]
Jacobson KA. Introduction to adenosine receptors as therapeutic targets. Handb Exp Pharmacol 2009; 193(193): 1-24.
[34]
Merighi S, Mirandola P, Varani K, et al. A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol Ther 2003; 100(1): 31-48.
[35]
Polosa R, Blackburn MR. Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease. Trends Pharmacol Sci 2009; 30(10): 528-35.
[36]
Baldwin JM. Structure and function of receptors coupled to G proteins. Curr Opin Cell Biol 1994; 6(2): 180-90.
[37]
Schöneberg T, Schulz A, Gudermann T. The structural basis of g-protein-coupled receptor function and dysfunction in human diseases. Rev Physiol Biochem Pharmacol 2002; 144-227.
[38]
Chabre M, le Maire M. Monomeric G-protein-coupled receptor as a functional unit. Biochemistry 2005; 44(27): 9395-403.
[39]
Ferré S, Baler R, Bouvier M, et al. Building a new conceptual framework for receptor heteromers. Nat Chem Biol 2009; 5(3): 131-4.
[40]
Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph 1996; 14(1): 33-38, 27-28.
[41]
Systèmes D. Discovery Studio 2017.
[42]
Jaakola V-P, Griffith MT, Hanson MA, et al. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 2008; 322(5905): 1211-7.
[43]
Cheng RKY, Segala E, Robertson N, et al. Structures of human A1 and A2A adenosine receptors with xanthines reveal determinants of selectivity. Structure 2017; 25(8): 1275-1285.e4.
[44]
Katritch V, Cherezov V, Stevens RC. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol Sci 2012; 33(1): 17-27.
[45]
Gao ZG, Kim SK, Ijzerman AP, Jacobson KA. Allosteric modulation of the adenosine family of receptors. Mini Rev Med Chem 2005; 5(6): 545-53.
[46]
Waterhouse A, Bertoni M, Bienert S, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 2018; 46(W1)W296-303
[47]
The PyMOL Molecular Graphics System. Schrödinger, LLC.
[48]
Hubbard RE. Structure-based Drug Discovery: An Overview 2006
[49]
Goodman JM. Chemistry RSo. Chemical Applications of Molecular Modelling 1998.
[50]
Cornell WD, Cieplak P, Bayly CI, et al. A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules. J Am Chem Soc 1995; 117(19): 5179-97.
[51]
Ponder JW, Case DA. Force fields for protein simulations. Adv Protein Chem 2003; 66: 27-85.
[52]
De Vivo M, Masetti M, Bottegoni G, Cavalli A. Role of Molecular Dynamics and Related Methods in Drug Discovery. J Med Chem 2016; 59(9): 4035-61.
[53]
Brooks BR, Brooks CL III, Mackerell AD Jr, et al. CHARMM: the biomolecular simulation program. J Comput Chem 2009; 30(10): 1545-614.
[54]
Oostenbrink C, Villa A, Mark AE, van Gunsteren WF. A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6. J Comput Chem 2004; 25(13): 1656-76.
[55]
Durrant JD, McCammon JA. Molecular dynamics simulations and drug discovery. BMC Biol 2011; 9(1): 71.
[56]
Liu X, Shi D, Zhou S, Liu H, Liu H, Yao X. Molecular dynamics simulations and novel drug discovery. Expert Opin Drug Discov 2018; 13(1): 23-37.
[57]
Borhani DW, Shaw DE. The future of molecular dynamics simulations in drug discovery. J Comput Aided Mol Des 2012; 26(1): 15-26.
[58]
Mortier J, Rakers C, Bermudez M, Murgueitio MS, Riniker S, Wolber G. The impact of molecular dynamics on drug design: Applications for the characterization of ligand-macromolecule complexes. Drug Discov Today 2015; 20(6): 686-702.
[59]
Ganesan A, Coote ML, Barakat K. Molecular dynamics-driven drug discovery: leaping forward with confidence. Drug Discov Today 2017; 22(2): 249-69.
[60]
Zhao H, Caflisch A. Molecular dynamics in drug design. Eur J Med Chem 2015; 91: 4-14.
[61]
Trincavelli ML, Daniele S, Martini C. Adenosine receptors: what we know and what we are learning. Curr Top Med Chem 2010; 10(9): 860-77.
[62]
Heifetz A, James T, Morao I, Bodkin MJ, Biggin PC. Guiding lead optimization with GPCR structure modeling and molecular dynamics. Curr Opin Pharmacol 2016; 30: 14-21.
[63]
Matricon P, Ranganathan A, Warnick E, et al. Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site. Sci Rep 2017; 7(1): 6398.
[64]
Moraes I, Evans G, Sanchez-Weatherby J, Newstead S, Stewart PDS. Membrane protein structure determination - the next generation. Biochim Biophys Acta 2014; 1838(1 Pt A)(1, Part A): 78-87.
[65]
Weyand S, Tate CG. Advances in membrane protein crystallography: in situ and in meso data collection. Acta Crystallogr D Biol Crystallogr 2015; 71(Pt 6): 1226-7.
[66]
Rucktooa P, Cheng RKY, Segala E, et al. Towards high throughput GPCR crystallography: In Meso soaking of Adenosine A2A Receptor crystals. Sci Rep 2018; 8(1): 41-1.
[67]
Jespers W, Schiedel AC, Heitman LH, et al. Structural mapping of adenosine receptor mutations: ligand binding and signaling mechanisms. Trends Pharmacol Sci 2018; 39(1): 75-89.
[68]
Segala E, Guo D, Cheng RKY, et al. Controlling the dissociation of ligands from the adenosine a2a receptor through modulation of salt bridge strength. J Med Chem 2016; 59(13): 6470-9.
[69]
Sun B, Bachhawat P, Chu ML-H, et al. Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket. Proc Natl Acad Sci USA 2017; 114(8): 2066-71.
[70]
Lebon G, Warne T, Edwards PC, et al. Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature 2011; 474(7352): 521-5.
[71]
Doré AS, Robertson N, Errey JC, et al. Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 2011; 19(9): 1283-93.
[72]
Carpenter B, Nehmé R, Warne T, Leslie AGW, Tate CG. Erratum: Structure of the adenosine A2A receptor bound to an engineered G protein. Nature 2016; 538(7626): 542
[73]
Lebon G, Edwards PC, Leslie AGW, Tate CG. Molecular determinants of CGS21680 binding to the human adenosine A2A receptor. Mol Pharmacol 2015; 87(6): 907-15.
[74]
Congreve M, Andrews SP, Doré AS, et al. Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure based drug design. J Med Chem 2012; 55(5): 1898-903.
[75]
Xu F, Wu H, Katritch V, et al. Structure of an agonist-bound human A2A adenosine receptor. Science 2011; 332(6027): 322-7.
[76]
Draper-Joyce CJ, Khoshouei M, Thal DM, et al. Structure of the adenosine-bound human adenosine A1 receptor-Gi complex. Nature 2018; 558(7711): 559-63.
[77]
Glukhova A, Thal DM, Nguyen AT, et al. Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 2017; 168(5): 867-877.e13.
[78]
McRobb FM, Negri A, Beuming T, Sherman W. Molecular dynamics techniques for modeling G protein-coupled receptors. Curr Opin Pharmacol 2016; 30: 69-75.
[79]
Ciancetta A, Sabbadin D, Federico S, Spalluto G, Moro S. Advances in computational techniques to study GPCR-ligand recognition. Trends Pharmacol Sci 2015; 36(12): 878-90.
[80]
Almeida JG, Preto AJ, Koukos PI, Bonvin AMJJ, Moreira IS. Membrane proteins structures: A review on computational modeling tools. Biochim Biophys Acta Biomembr 2017; 1859(10): 2021-39.
[81]
Seifert R, Wenzel-Seifert K. Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch Pharmacol 2002; 366(5): 381-416.
[82]
Rosenbaum DM, Rasmussen SGF, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature 2009; 459(7245): 356-63.
[83]
Sato J, Makita N, Iiri T. Inverse agonism: the classic concept of GPCRs revisited. Endocr J 2016; 63(6): 507-14.
[84]
Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S. Action of molecular switches in GPCRs--theoretical and experimental studies. Curr Med Chem 2012; 19(8): 1090-109.
[85]
Piirainen H, Ashok Y, Nanekar RT, Jaakola V-P. Structural features of adenosine receptors: from crystal to function. Biochim Biophys Acta 2011; 1808(5): 1233-44.
[86]
Gutiérrez-de-Terán H, Centeno NB, Pastor M, Sanz F. Novel approaches for modeling of the A1 adenosine receptor and its agonist binding site. Proteins 2004; 54(4): 705-15.
[87]
Gutiérrez-de-Terán H, Pastor M, Centeno NB, Åqvist J, Sanz F. Comparative analysis of putative agonist-binding modes in the human A1 adenosine receptor. ChemBioChem 2004; 5(6): 841-9.
[88]
Hallmen C, Wiese M. Molecular dynamics simulation of the human adenosine A3 receptor: Agonist induced conformational changes of Trp243. J Comput Aided Mol Des 2006; 20(10-11): 673-84.
[89]
Nakayama TA, Khorana HG. Mapping of the amino acids in membrane-embedded helices that interact with the retinal chromophore in bovine rhodopsin. J Biol Chem 1991; 266(7): 4269-75.
[90]
Gao Z-G, Chen A, Barak D, Kim SK, Müller CE, Jacobson KA. Identification by site-directed mutagenesis of residues involved in ligand recognition and activation of the human A3 adenosine receptor. J Biol Chem 2002; 277(21): 19056-63.
[91]
Vogel R, Mahalingam M, Lüdeke S, Huber T, Siebert F, Sakmar TP. Functional role of the “ionic lock”--an interhelical hydrogen-bond network in family A heptahelical receptors. J Mol Biol 2008; 380(4): 648-55.
[92]
Schneider EH, Schnell D, Strasser A, Dove S, Seifert R. Impact of the DRY motif and the missing “ionic lock” on constitutive activity and G-protein coupling of the human histamine H4 receptor. J Pharmacol Exp Ther 2010; 333(2): 382-92.
[93]
Xie X-Q, Chowdhury A. Advances in methods to characterize ligand-induced ionic lock and rotamer toggle molecular switch in G protein-coupled receptors. Methods Enzymol 2013; 520: 153-74.
[94]
Jójárt B, Kiss R, Viskolcz B, Kolossváry I, Keserű GM. Molecular dynamics simulation at high sodium chloride concentration: toward the inactive conformation of the human adenosine A2A receptor. J Phys Chem Lett 2010; 1(6): 1008-13.
[95]
Dror RO, Arlow DH, Borhani DW, Jensen M, Shaw DE. Identification Of Two Distinct Inactive Conformations Of The Beta-2 Adrenergic Receptor Reconciles Structural And Biochemical Observations. Biophys J 2009; 96(3): 365a.
[96]
Rodríguez D, Piñeiro Á, Gutiérrez-de-Terán H. Molecular dynamics simulations reveal insights into key structural elements of adenosine receptors. Biochemistry 2011; 50(19): 4194-208.
[97]
Lee JY, Lyman E. Agonist dynamics and conformational selection during microsecond simulations of the A(2A) adenosine receptor. Biophys J 2012; 102(9): 2114-20.
[98]
Li J, Jonsson AL, Beuming T, Shelley JC, Voth GA. Ligand-dependent activation and deactivation of the human adenosine A(2A) receptor. J Am Chem Soc 2013; 135(23): 8749-59.
[99]
Laio A, Parrinello M. Escaping free-energy minima. Proc Natl Acad Sci USA 2002; 99(20): 12562-6.
[100]
Barducci A, Bonomi M, Parrinello M. Metadynamics. Wiley Interdiscip Rev Comput Mol Sci 2011; 1(5): 826-43.
[101]
Liu W, Chun E, Thompson AA, et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science 2012; 337(6091): 232-6.
[102]
Martínez-Archundia M, Correa-Basurto J. Molecular dynamics simulations reveal initial structural and dynamic features for the A2AR as a result of ligand binding. Mol Simul 2014; 40(13): 996-1014.
[103]
Yuan S, Filipek S, Palczewski K, Vogel H. Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway. Nat Commun 2014; 5: 4733.
[104]
Yuan S, Hu Z, Filipek S, Vogel H. W246(6.48) opens a gate for a continuous intrinsic water pathway during activation of the adenosine A2A receptor. Angew Chem Int Ed Engl 2015; 54(2): 556-9.
[105]
Strange PG. Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors. Br J Pharmacol 2008; 153(7): 1353-63.
[106]
Cusack KP, Wang Y, Hoemann MZ, Marjanovic J, Heym RG, Vasudevan A. Design strategies to address kinetics of drug binding and residence time. Bioorg Med Chem Lett 2015; 25(10): 2019-27.
[107]
Guo D, Hillger JM, IJzerman AP, Heitman LH. Drug-target residence time--a case for G protein-coupled receptors. Med Res Rev 2014; 34(4): 856-92.
[108]
Guo D, Mulder-Krieger T, IJzerman AP, Heitman LH. Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time. Br J Pharmacol 2012; 166(6): 1846-59.
[109]
Guo D, Pan AC, Dror RO, et al. Molecular Basis of Ligand Dissociation from the Adenosine A2A Receptor. Mol Pharmacol 2016; 89(5): 485-91.
[110]
Maragliano L, Vanden-Eijnden E. A temperature accelerated method for sampling free energy and determining reaction pathways in rare events simulations. Chem Phys Lett 2006; 426(1): 168-75.
[111]
Fenton AW. Allostery: An illustrated definition for the ‘second secret of life’. Trends Biochem Sci 2008; 33(9): 420-5.
[112]
Monod J, Wyman J, Changeux J-P. On the nature of allosteric transitions: A plausible model. J Mol Biol 1965; 12(1): 88-118.
[113]
Kenakin TP. '7TM receptor allostery: putting numbers to shapeshifting proteins. Trends Pharmacol Sci 2009; 30(9): 460-9.
[114]
Durdagi S, Erol I, Salmas RE, Aksoydan B, Kantarcioglu I. Oligomerization and cooperativity in GPCRs from the perspective of the angiotensin AT1 and dopamine D2 receptors. Neurosci Lett 2018; 20(18): 20.
[115]
Milligan G. G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol 2009; 158(1): 5-14.
[116]
Whorton MR, Bokoch MP, Rasmussen SGF, et al. A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc Natl Acad Sci USA 2007; 104(18): 7682-7.
[117]
Bayburt TH, Vishnivetskiy SA, McLean MA, et al. Monomeric rhodopsin is sufficient for normal rhodopsin kinase (GRK1) phosphorylation and arrestin-1 binding. J Biol Chem 2011; 286(2): 1420-8.
[118]
Pin J-P, Galvez T, Prézeau L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther 2003; 98(3): 325-54.
[119]
Harikumar KG, Morfis MM, Sexton PM, Miller LJ. Pattern of intra-family hetero-oligomerization involving the G-protein-coupled secretin receptor j Mol Neurosci 2008. 36(0)
[120]
Smith NJ, Milligan G. Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes. Pharmacol Rev 2010; 62(4): 701-25.
[121]
van der Klein PAM, Kourounakis AP, IJzerman AP. Allosteric modulation of the adenosine A(1) receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding. J Med Chem 1999; 42(18): 3629-35.
[122]
Welihinda AA, Amento EP. Positive allosteric modulation of the adenosine A2a receptor attenuates inflammation. J Inflamm (Lond) 2014; 11(1): 37.
[123]
Trincavelli ML, Giacomelli C, Daniele S, et al. Allosteric modulators of human A2B adenosine receptor BBA General subjects 2014. 1840(3): 1194-203.
[124]
Gao Z-G, Van Muijlwijk-Koezen JE, Chen A, Müller CE, Ijzerman AP, Jacobson KA. Allosteric modulation of A(3) adenosine receptors by a series of 3-(2-pyridinyl)isoquinoline derivatives. Mol Pharmacol 2001; 60(5): 1057-63.
[125]
Göblyös A, Ijzerman AP. Allosteric modulation of adenosine receptors. Purinergic Signal 2009; 5(1): 51-61.
[126]
La Motta C, Sartini S, Morelli M, Taliani S, Da Settimo F. Allosteric modulators for adenosine receptors: An alternative to the orthosteric ligands. Curr Top Med Chem 2010; 10(10): 976-92.
[127]
Göblyös A, Ijzerman AP. Allosteric modulation of adenosine receptors. Biochim Biophys Acta 2011; 1808(5): 1309-18.
[128]
Kimatrai-Salvador M, Baraldi PG, Romagnoli R. Allosteric modulation of A1-adenosine receptor: A review. Drug Discov Today Technol 2013; 10(2): e285-96.
[129]
Nikbin N, Edwards C, Reynolds CA. G-protein Coupled Receptor Dimerization. IJPT 2003; 2(1): 1-11.
[130]
Franco R, Casadó V, Mallol J, et al. The two-state dimer receptor model: A general model for receptor dimers. Mol Pharmacol 2006; 69(6): 1905-12.
[131]
May LT, Bridge LJ, Stoddart LA, Briddon SJ, Hill SJ. Allosteric interactions across native adenosine-A3 receptor homodimers: quantification using single-cell ligand-binding kinetics. FASEB J 2011; 25(10): 3465-76.
[132]
Hill SJ, May LT, Kellam B, Woolard J. Allosteric interactions at adenosine A(1) and A(3) receptors: new insights into the role of small molecules and receptor dimerization. Br J Pharmacol 2014; 171(5): 1102-13.
[133]
Franco R, Martínez-Pinilla E, Lanciego JL, Navarro G. Basic pharmacological and structural evidence for class A G-protein-coupled receptor heteromerization. Front Pharmacol 2016; 7(76): 76.
[134]
Soriano A, Ventura R, Molero A, et al. Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A2A-D2 receptor heteromers. J Med Chem 2009; 52(18): 5590-602.
[135]
Jörg M, May LT, Mak FS, et al. Synthesis and pharmacological evaluation of dual acting ligands targeting the adenosine A2A and dopamine D2 receptors for the potential treatment of Parkinson’s disease. J Med Chem 2015; 58(2): 718-38.
[136]
Cottet M, Faklaris O, Maurel D, et al. BRET and Time-resolved FRET strategy to study GPCR oligomerization: from cell lines toward native tissues. Front Endocrinol 2012; 3(92): 92.
[137]
Guo H, An S, Ward R, et al. Methods used to study the oligomeric structure of G-protein-coupled receptors. Biosci Rep 2017; 37(2)BSR20160547
[138]
Gahbauer S, Böckmann RA. Membrane-mediated oligomerization of G protein coupled receptors and its implications for GPCR function. Front Physiol 2016; 7(494): 494.
[139]
Kim S-K, Jacobson KA. Computational prediction of homodimerization of the A3 adenosine receptor. J Mol Graph Model 2006; 25(4): 549-61.
[140]
Fanelli F, Felline A. Dimerization and ligand binding affect the structure network of A(2A) adenosine receptor. Biochim Biophys Acta 2011; 1808(5): 1256-66.
[141]
Chen R, Weng Z. A novel shape complementarity scoring function for protein-protein docking. Proteins 2003; 51(3): 397-408.
[142]
Im W, Feig M, Brooks CL III. An implicit membrane generalized born theory for the study of structure, stability, and interactions of membrane proteins. Biophys J 2003; 85(5): 2900-18.
[143]
Vishveshwara S, Brinda KV, Kannan N. Protein structure: insights from graph theory. J Theor Comput Chem 2002; 01(01): 187-211.
[144]
Guixà-González R, Javanainen M, Gómez-Soler M, et al. Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors. Sci Rep 2016; 6: 19839.
[145]
Merchant BA, Madura JD. A review of coarse-grained molecular dynamics techniques to access extended spatial and temporal scales in biomolecular simulations.annual reports in computational chemistry 2011; 67-87.
[146]
Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH. The MARTINI force field: coarse grained model for biomolecular simulations. J Phys Chem B 2007; 111(27): 7812-24.
[147]
Innis SM. Dietary omega 3 fatty acids and the developing brain. Brain Res 2008; 1237: 35-43.
[148]
Calon F, Cole G. Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot Essent Fatty Acids 2007; 77(5-6): 287-93.
[149]
Taha AY, Cheon Y, Ma K, Rapoport SI, Rao JS. Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients. J Psychiatr Res 2013; 47(5): 636-43.
[150]
Martín V, Fabelo N, Santpere G, et al. Lipid alterations in lipid rafts from Alzheimer’s disease human brain cortex. J Alzheimers Dis 2010; 19(2): 489-502.
[151]
Fabelo N, Martín V, Santpere G, et al. Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol Med 2011; 17(9-10): 1107-18.
[152]
Fuxe K, Marcellino D, Genedani S, Agnati L. Adenosine A(2A) receptors, dopamine D(2) receptors and their interactions in Parkinson’s disease. Mov Disord 2007; 22(14): 1990-2017.
[153]
Gawrisch K, Soubias O, Mihailescu M. Insights from biophysical studies on the role of polyunsaturated fatty acids for function of G-protein coupled membrane receptors. Prostaglandins Leukot Essent Fatty Acids 2008; 79(3-5): 131-4.
[154]
Mitchell DC, Niu S-L, Litman BJ. Enhancement of G protein-coupled signaling by DHA phospholipids. Lipids 2003; 38(4): 437-43.
[155]
Altwaijry NA, Baron M, Wright DW, Coveney PV, Townsend-Nicholson A. An ensemble-based protocol for the computational prediction of helix-helix interactions in g protein-coupled receptors using coarse-grained molecular dynamics. J Chem Theory Comput 2017; 13(5): 2254-70.
[156]
Thévenin D, Lazarova T. Stable interactions between the transmembrane domains of the adenosine A2A receptor. Protein Sci 2008; 17(7): 1188-99.
[157]
Fuxe K, Marcellino D, Borroto-Escuela DO, et al. Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neurosci Ther 2010; 16(3): e18-42.
[158]
Ferre S, von Euler G, Johansson B, Fredholm BB, Fuxe K. Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci USA 1991; 88(16): 7238-41.
[159]
Borroto-Escuela DO, Pintsuk J, Schäfer T, et al. Multiple D2 heteroreceptor complexes: new targets for treatment of schizophrenia. Ther Adv Psychopharmacol 2016; 6(2): 77-94.
[160]
Borroto-Escuela DO, Rodriguez D, Romero-Fernandez W, et al. Mapping the interface of a GPCR dimer: A structural model of the A2A adenosine and D2 dopamine receptor heteromer. Front Pharmacol 2018; 9(829): 829.
[161]
Lee Y, Choi S, Hyeon C. Mapping the intramolecular signal transduction of G-protein coupled receptors. Proteins 2014; 82(5): 727-43.
[162]
Nygaard R, Frimurer TM, Holst B, Rosenkilde MM, Schwartz TW. Ligand binding and micro-switches in 7TM receptor structures. Trends Pharmacol Sci 2009; 30(5): 249-59.
[163]
Rasmussen SGF, DeVree BT, Zou Y, et al. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 2011; 477(7366): 549-55.
[164]
Albert R, Jeong H, Barabási A-L. Error and attack tolerance of complex networks. Nature 2000; 406(6794): 378-82.
[165]
Lee Y, Choi S, Hyeon C. Communication over the network of binary switches regulates the activation of A2A adenosine receptor. PLOS Comput Biol 2015; 11(2)e1004044
[166]
Lee Y, Kim S, Choi S, Hyeon C. Ultraslow water-mediated transmembrane interactions regulate the activation of A2A adenosine receptor. Biophys J 2016; 111(6): 1180-91.
[167]
Dunn MF. Protein-Ligand Interactions: General Description. Encyclopedia of life sciences 2001
[168]
Pan AC, Borhani DW, Dror RO, Shaw DE. Molecular determinants of drug-receptor binding kinetics. Drug Discov Today 2013; 18(13-14): 667-73.
[169]
IJzerman AP, Von Frijtag Drabbe Künzel JK, Kim J, Jiang Q, Jacobson KA. Site-directed mutagenesis of the human adenosine A2A receptor. Critical involvement of Glu13 in agonist recognition. Eur J Pharmacol 1996; 310(2-3): 269-72.
[170]
Jiang Q, Lee BX, Glashofer M, van Rhee AM, Jacobson KA. Mutagenesis reveals structure-activity parallels between human A2A adenosine receptors and biogenic amine G protein-coupled receptors. J Med Chem 1997; 40(16): 2588-95.
[171]
Buch I, Giorgino T, De Fabritiis G. Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations. Proc Natl Acad Sci USA 2011; 108(25): 10184-9.
[172]
Johnston JM, Filizola M. Beyond standard molecular dynamics: investigating the molecular mechanisms of G protein-coupled receptors with enhanced molecular dynamics methods. Adv Exp Med Biol 2014; 796: 95-125.
[173]
Sabbadin D, Moro S. Supervised molecular dynamics (SuMD) as a helpful tool to depict GPCR-ligand recognition pathway in a nanosecond time scale. J Chem Inf Model 2014; 54(2): 372-6.
[174]
Kim J, Wess J, van Rhee AM, Schöneberg T, Jacobson KA. Site-directed mutagenesis identifies residues involved in ligand recognition in the human A2a adenosine receptor. J Biol Chem 1995; 270(23): 13987-97.
[175]
Sabbadin D, Ciancetta A, Deganutti G, Cuzzolin A, Moro S. Exploring the recognition pathway at the human A2A adenosine receptor of the endogenous agonist adenosine using supervised molecular dynamics simulations. MedChemComm 2015; 6(6): 1081-5.
[176]
Deganutti G, Cuzzolin A, Ciancetta A, Moro S. 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. Bioorg Med Chem 2015; 23(14): 4065-71.
[177]
Kim Y, de Castro S, Gao Z-G, Ijzerman AP, Jacobson KA. Novel 2- and 4-substituted 1H-imidazo [4,5-c]quinolin-4-amine derivatives as allosteric modulators of the A3 adenosine receptor. J Med Chem 2009; 52(7): 2098-108.
[178]
Cuzzolin A, Sturlese M, Deganutti G, et al. Deciphering the complexity of ligand-protein recognition pathways using supervised molecular dynamics (SuMD) simulations. J Chem Inf Model 2016; 56(4): 687-705.
[179]
Keränen H, Gutiérrez-de-Terán H, Åqvist J. Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding. PLoS One 2014; 9(10)e108492
[180]
Deganutti G, Welihinda A, Moro S. Comparison of the human A2A adenosine receptor recognition by adenosine and Inosine: New insight from supervised molecular dynamics simulations. ChemMedChem 2017; 12(16): 1319-26.
[181]
Hilser VJ. Biochemistry. An ensemble view of allostery. Science 2010; 327(5966): 653-4.
[182]
Tsai C-J, del Sol A, Nussinov R. Allostery: Absence of a change in shape does not imply that allostery is not at play. J Mol Biol 2008; 378(1): 1-11.
[183]
Fenton AW. Allostery: An illustrated definition for the ‘second secret of life’. Trends Biochem Sci 2008; 33(9): 420-5.
[184]
Christopoulos A, Kenakin T. G protein-coupled receptor allosterism and complexing. Pharmacol Rev 2002; 54(2): 323-74.
[185]
Cui Q, Karplus M. Allostery and cooperativity revisited. Protein Sci 2008; 17(8): 1295-307.
[186]
Kar G, Keskin O, Gursoy A, Nussinov R. Allostery and population shift in drug discovery. Curr Opin Pharmacol 2010; 10(6): 715-22.
[187]
Gunasekaran K, Ma Buyong. Bioinf 2004; 57: 433-43.
[188]
Lee JY, Lyman E. Predictions for cholesterol interaction sites on the A2A adenosine receptor. J Am Chem Soc 2012; 134(40): 16512-5.
[189]
Sengupta D, Chattopadhyay A. Identification of cholesterol binding sites in the serotonin1A receptor. J Phys Chem B 2012; 116(43): 12991-6.
[190]
Prasanna X, Chattopadhyay A, Sengupta D. Cholesterol modulates the dimer interface of the β2-adrenergic receptor via cholesterol occupancy sites. Biophys J 2014; 106(6): 1290-300.
[191]
Cang X, Du Y, Mao Y, Wang Y, Yang H, Jiang H. Mapping the functional binding sites of cholesterol in β2-adrenergic receptor by long-time molecular dynamics simulations. J Phys Chem B 2013; 117(4): 1085-94.
[192]
Sengupta D, Chattopadhyay A. Molecular dynamics simulations of GPCR-cholesterol interaction: An emerging paradigm. Biochim Biophys Acta 2015; 1848(9): 1775-82.
[193]
Lee JY, Patel R, Lyman E. Ligand-dependent cholesterol interactions with the human A(2A) adenosine receptor. Chem Phys Lipids 2013; 169: 39-45.
[194]
Gutiérrez-de-Terán H, Massink A, Rodríguez D, et al. The role of a sodium ion binding site in the allosteric modulation of the A(2A) adenosine G protein-coupled receptor. Structure 2013; 21(12): 2175-85.
[195]
Massink A, Gutiérrez-de-Terán H, Lenselink EB, et al. Sodium ion binding pocket mutations and adenosine A2A receptor function. Mol Pharmacol 2015; 87(2): 305-13.
[196]
Nguyen ATN, Baltos J-A, Thomas T, et al. Extracellular loop 2 of the adenosine A1 receptor has a key role in orthosteric ligand affinity and agonist efficacy. Mol Pharmacol 2016; 90(6): 703-14.
[197]
Nguyen ATN, Vecchio EA, Thomas T, et al. Role of the second extracellular loop of the adenosine A1 receptor on allosteric modulator binding, signaling, and cooperativity. Mol Pharmacol 2016; 90(6): 715-25.
[198]
Deganutti G, Moro S. Supporting the identification of novel fragment-based positive allosteric modulators using a supervised molecular dynamics approach: a retrospective analysis considering the human A2A adenosine receptor as a key example. Molecules 2017; 22(5): 818.
[199]
Chen D, Errey JC, Heitman LH, Marshall FH, Ijzerman AP, Siegal G. Fragment screening of GPCRs using biophysical methods: identification of ligands of the adenosine A(2A) receptor with novel biological activity. ACS Chem Biol 2012; 7(12): 2064-73.
[200]
Song W, Yen H-Y, Robinson CV, Sansom M. State-dependent lipid interactions with the A2a receptor revealed by MD simulations using in vivo-mimetic membranes. bioRxiv 2018.
[201]
Yen H-Y, Hoi KK, Liko I, et al. PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling. Nature 2018; 559(7714): 423-7.
[202]
Cappel D, Wahlström R, Brenk R, Sotriffer CA. Probing the dynamic nature of water molecules and their influences on ligand binding in a model binding site. J Chem Inf Model 2011; 51(10): 2581-94.
[203]
Lu Y, Wang R, Yang C-Y, Wang S. Analysis of ligand-bound water molecules in high-resolution crystal structures of protein-ligand complexes. J Chem Inf Model 2007; 47(2): 668-75.
[204]
Snyder PW, Mecinović J, Moustakas DT, et al. Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase. Proc Natl Acad Sci USA 2011; 108(44): 17889-94.
[205]
Mason JS, Bortolato A, Weiss DR, et al. High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks. In Silico Pharmacol 2013; 1: 23.
[206]
Baroni M, Cruciani G, Sciabola S, Perruccio F, Mason JS. A common reference framework for analyzing/comparing proteins and ligands. Fingerprints for Ligands and Proteins (FLAP): theory and application. J Chem Inf Model 2007; 47(2): 279-94.
[207]
Abel R, Young T, Farid R, Berne BJ, Friesner RA. Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. J Am Chem Soc 2008; 130(9): 2817-31.
[208]
Young T, Abel R, Kim B, Berne BJ, Friesner RA. Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding. Proc Natl Acad Sci USA 2007; 104(3): 808-13.
[209]
Sabbadin D, Ciancetta A, Moro S. Perturbation of fluid dynamics properties of water molecules during G protein-coupled receptor-ligand recognition: the human A2A adenosine receptor as a key study. J Chem Inf Model 2014; 54(10): 2846-55.
[210]
Borodovsky A, Wang Y, Ye M, et al. Abstract 3751: Inhibition of A2AR by AZD4635 induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical models. Cancer Res 2018; 78(13)(Suppl.): 3751.
[211]
Jazayeri A, Andrews SP, Marshall FH. Structurally enabled discovery of adenosine A2A receptor antagonists. Chem Rev 2017; 117(1): 21-37.
[212]
Baldwin PA, Hubbell WL. Effects of lipid environment on the light-induced conformational changes of rhodopsin. 2. Roles of lipid chain length, unsaturation, and phase state. Biochemistry 1985; 24(11): 2633-9.
[213]
Brown MF. Modulation of rhodopsin function by properties of the membrane bilayer. Chem Phys Lipids 1994; 73(1-2): 159-80.
[214]
Grossfield A. Recent progress in the study of G protein-coupled receptors with molecular dynamics computer simulations. Biochim Biophys Acta 2011; 1808(7): 1868-78.
[215]
Ivanov AA, Baskin II, Palyulin VA, Piccagli L, Baraldi PG, Zefirov NS. Molecular modeling and molecular dynamics simulation of the human A2B adenosine receptor. The study of the possible binding modes of the A2B receptor antagonists. J Med Chem 2005; 48(22): 6813-20.
[216]
Baraldi PG, Tabrizi MA, Preti D, et al. Design, synthesis, and biological evaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists. J Med Chem 2004; 47(6): 1434-47.
[217]
Lyman E, Higgs C, Kim B, et al. A role for a specific cholesterol interaction in stabilizing the Apo configuration of the human A(2A) adenosine receptor. Structure 2009; 17(12): 1660-8.
[218]
Hanson MA, Cherezov V, Griffith MT, et al. A specific cholesterol binding site is established by the 2.8 A structure of the human β2-adrenergic receptor. Structure 2008; 16(6): 897-905.
[219]
Grossfield A, Feller SE, Pitman MC. A role for direct interactions in the modulation of rhodopsin by ω-3 polyunsaturated lipids. Proc Natl Acad Sci USA 2006; 103(13): 4888-93.
[220]
Mansourian M, Madadkar-Sobhani A, Mahnam K, Fassihi A, Saghaie L. Characterization of adenosine receptor in its native environment: insights from molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A(2B) adenosine receptor. J Mol Model 2012; 18(9): 4309-24.
[221]
Mansourian M, Mahnam K, Madadkar-Sobhani A, Fassihi A, Saghaie L. Insights into the human A1 adenosine receptor from molecular dynamics simulation: structural study in the presence of lipid membrane. Med Chem Res 2015; 24(10): 3645-59.
[222]
Olah ME, Ren H, Ostrowski J, Jacobson KA, Stiles GL. Cloning, expression, and characterization of the unique bovine A1 adenosine receptor. Studies on the ligand binding site by site-directed mutagenesis. J Biol Chem 1992; 267(15): 10764-70.
[223]
Ng HW, Laughton CA, Doughty SW. Molecular dynamics simulations of the adenosine A2a receptor in POPC and POPE lipid bilayers: effects of membrane on protein behavior. J Chem Inf Model 2014; 54(2): 573-81.
[224]
Cao R, Rossetti G, Bauer A. CarIoni P. Binding of the antagonist caffeine to the human adenosine receptor hA2AR in nearly physiological conditions. PLoS One 2015; 10(5)e0126833
[225]
Boukharta L, Gutiérrez-de-Terán H, Åqvist J. Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors. PLOS Comput Biol 2014; 10(4)e1003585
[226]
Jespers W, Oliveira A, Prieto-Díaz R, et al. Structure-based design of potent and selective ligands at the four adenosine receptors. Molecules 2017; 22(11)E1945
[227]
Pitera JW, van Gunsteren WF. A comparison of non-bonded scaling approaches for free energy calculations. Mol Simul 2002; 28(1-2): 45-65.
[228]
Bharate SB, Singh B, Kachler S, et al. Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo [5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A2A Adenosine Receptor: Prediction from Molecular Modeling. J Med Chem 2016; 59(12): 5922-8.
[229]
Crespo A, El Maatougui A, Biagini P, et al. Discovery of 3,4-dihydropyrimidin-2(1H)-ones as a novel class of potent and selective A2B adenosine receptor antagonists. ACS Med Chem Lett 2013; 4(11): 1031-6.
[230]
Yaziji V, Rodríguez D, Gutiérrez-de-Terán H, et al. Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists. J Med Chem 2011; 54(2): 457-71.
[231]
Azuaje J, Jespers W, Yaziji V, et al. Effect of nitrogen atom substitution in A3 adenosine receptor binding: N-(4,6-diarylpyridin-2-yl)acetamides as potent and selective antagonists. J Med Chem 2017; 60(17): 7502-11.
[232]
Wang L, Wu Y, Deng Y, et al. Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field. J Am Chem Soc 2015; 137(7): 2695-703.
[233]
Abel R, Wang L, Harder ED, Berne BJ, Friesner RA. Advancing drug discovery through enhanced free energy calculations. Acc Chem Res 2017; 50(7): 1625-32.
[234]
Meng X-Y, Zhang H-X, Mezei M, Cui M. Molecular docking: A powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des 2011; 7(2): 146-57.
[235]
David L, Nielsen PA, Hedstrom M, Norden B. Scope and limitation of ligand docking: methods, scoring functions and protein targets. Curr Comput Aided Drug Des 2005; 1(3): 275-306.
[236]
Bartuzi D, Kaczor AA, Targowska-Duda KM, Matosiuk D. Recent advances and applications of molecular docking to G protein-coupled receptors. Molecules 2017; 22(2)E340
[237]
Sabbadin D, Ciancetta A, Moro S. Bridging molecular docking to membrane molecular dynamics to investigate GPCR-ligand recognition: the human A2A adenosine receptor as a key study. J Chem Inf Model 2014; 54(1): 169-83.
[238]
Federico S, Ciancetta A, Sabbadin D, et al. Exploring the directionality of 5-substitutions in a new series of 5-alkylaminopyrazolo [4,3-e]1,2,4-triazolo [1,5-c]pyrimidine as a strategy to design novel human a(3) adenosine receptor antagonists. J Med Chem 2012; 55(22): 9654-68.
[239]
Pran Kishore D, Balakumar C, Raghuram Rao A, Roy PP, Roy K. QSAR of adenosine receptor antagonists: Exploring physicochemical requirements for binding of pyrazolo [4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine derivatives with human adenosine A(3) receptor subtype. Bioorg Med Chem Lett 2011; 21(2): 818-23.
[240]
Chandrasekaran B, Deb PK, Kachler S, et al. Synthesis and adenosine receptors binding studies of new fluorinated analogues of pyrido [2,3-d]pyrimidines and quinazolines. Med Chem Res 2018; 27(3): 756-67.
[241]
Deb PK, Mailavaram R, Chandrasekaran B, et al. Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno [2,3-d]pyrimidine derivatives. Chem Biol Drug Des 2018; 91(4): 962-9.


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