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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

Author(s): Pabitra Narayan Samanta, Supratik Kar* and Jerzy Leszczynski*

Volume 25, Issue 7, 2019

Page: [750 - 773] Pages: 24

DOI: 10.2174/1381612825666190304123545

Price: $65

Abstract

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

Keywords: Adenosine receptor, GPCR, In silico, Molecular Dynamics, QSAR, macromolecular systems.

[1]
Fredholm BB, IJzerman AP, Jacobson KA, Klotz K-N, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001; 53(4): 527-52.
[2]
Jacobson KA, Gao Z-G. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 2006; 5(3): 247-64.
[3]
Baraldi PG, Tabrizi MA, Gessi S, Borea PA. Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility. Chem Rev 2008; 108(1): 238-63.
[4]
Müller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 2011; 1808(5): 1290-308.
[5]
Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE, 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.
[6]
Zhou X, Teng B, Tilley S, Mustafa SJA. A1 adenosine receptor negatively modulates coronary reactive hyperemia via counteracting A2A-mediated H2O2 production and KATP opening in isolated mouse hearts. Am J Physiol Heart Circ Physiol 2013; 305(11): H1668-79.
[7]
Gross GJ, Hardman HF, Warltier DC. Adenosine on myocardial oxygen consumption. Br J Pharmacol 1976; 57(3): 409-12.
[8]
Ham J, Rees DA. The adenosine a2b receptor: its role in inflammation. Endocr Metab Immune Disord Drug Targets 2008; 8(4): 244-54.
[9]
Haskó G, Pacher P. Regulation of macrophage function by adenosine. Arterioscler Thromb Vasc Biol 2012; 32(4): 865-9.
[10]
Jacobson KA. Crystal structures of the A2A adenosine receptor and their use in medicinal chemistry. In Silico Pharmacol 2013; 1: 22.
[11]
Jaakola VP, 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.
[12]
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.
[13]
Hino T, Arakawa T, Iwanari H, et al. G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody. Nature 2012; 482(7384): 237-40.
[14]
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.
[15]
Liu W, Chun E, Thompson AA, et al. Structural basis for allosteric regulation of GPCRs by sodium ions. Science 2012; 337(6091): 232-6.
[16]
Schenone S, Brullo C, Musumeci F, Bruno O, Botta M. A1 receptors ligands: past, present and future trends. Curr Top Med Chem 2010; 10(9): 878-901.
[17]
Baraldi PG, Tabrizi MA, Bovero A, et al. Recent developments in the field of A2A and A3 adenosine receptor antagonists. Eur J Med Chem 2003; 38(4): 367-82.
[18]
Varani K, Abbracchio MP, Cannella M, et al. Aberrant A2A receptor function in peripheral blood cells in Huntington’s disease. FASEB J 2003; 17(14): 2148-50.
[19]
Flögel U, Burghoff S, van Lent PLEM, et al. Selective activation of adenosine A2A receptors on immune cells by a CD73-dependent prodrug suppresses joint inflammation in experimental rheumatoid arthritis. Sci Transl Med 2012; 4(146)146ra108
[20]
Stössel A, Schlenk M, Hinz S, et al. Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones. J Med Chem 2013; 56(11): 4580-96.
[21]
de Lera Ruiz M, Lim YH, Zheng J. Adenosine A2A receptor as a drug discovery target. J Med Chem 2014; 57(9): 3623-50.
[22]
Gnad T, Scheibler S, von Kügelgen I, et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 2014; 516(7531): 395-9.
[23]
Holgate ST. The Quintiles Prize Lecture 2004. The identification of the adenosine A2B receptor as a novel therapeutic target in asthma. Br J Pharmacol 2005; 145(8): 1009-15.
[24]
Linden J. New insights into the regulation of inflammation by adenosine. J Clin Invest 2006; 116(7): 1835-7.
[25]
Ortore G, Martinelli A. A2B receptor ligands: past, present and future trends. Curr Top Med Chem 2010; 10(9): 923-40.
[26]
Liang BT, Jacobson KA. A physiological role of the adenosine A3 receptor: sustained cardioprotection. Proc Natl Acad Sci USA 1998; 95(12): 6995-9.
[27]
Akkari R, Burbiel JC, Hockemeyer J, Müller CE. Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs. Curr Top Med Chem 2006; 6(13): 1375-99.
[28]
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.
[29]
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.
[30]
Baraldi PG, Preti D, Borea PA, Varani K. Medicinal chemistry of A3 adenosine receptor modulators: pharmacological activities and therapeutic implications. J Med Chem 2012; 55(12): 5676-703.
[31]
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.
[32]
Borea PA, Varani K, Vincenzi F, et al. The A3 adenosine receptor: history and perspectives. Pharmacol Rev 2015; 67(1): 74-102.
[33]
Jacobson KA, Civan MM. Ocular Purine Receptors as Drug Targets in the Eye. J Ocul Pharmacol Ther 2016; 32(8): 534-47.
[34]
van Westen GJP, van den Hoven OO, van der Pijl R, et al. Identifying novel adenosine receptor ligands by simultaneous proteochemometric modeling of rat and human bioactivity data. J Med Chem 2012; 55(16): 7010-20.
[35]
Sirci F, Goracci L, Rodríguez D, van Muijlwijk-Koezen J, Gutiérrez-de-Terán H, Mannhold R. Ligand-, structure- and pharmacophore-based molecular fingerprints: a case study on adenosine A(1), A (2A), A (2B), and A (3) receptor antagonists. J Comput Aided Mol Des 2012; 26(11): 1247-66.
[36]
Kolb P, Phan K, Gao ZG, Marko AC, Sali A, Jacobson KA. Limits of ligand selectivity from docking to models: in silico screening for A(1) adenosine receptor antagonists. PLoS One 2012; 7(11)e49910
[37]
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.
[38]
Jazayeri A, Andrews SP, Marshall FH. Structurally enabled discovery of adenosine A2A receptor antagonists. Chem Rev 2017; 117(1): 21-37.
[39]
Gutiérrez-de-Terán H, Sallander J, Sotelo E. Structure-based rational design of adenosine receptor ligands. Curr Top Med Chem 2017; 17(1): 40-58.
[40]
Jaakola VP, Lane JR, Lin JY, Katritch V, Ijzerman AP, Stevens RC. Ligand binding and subtype selectivity of the human A(2A) adenosine receptor: identification and characterization of essential amino acid residues. J Biol Chem 2010; 285(17): 13032-44.
[41]
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.
[42]
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.
[43]
Carlsson J, Yoo L, Gao ZG, Irwin JJ, Shoichet BK, Jacobson KA. Structure-based discovery of A2A adenosine receptor ligands. J Med Chem 2010; 53(9): 3748-55.
[44]
Katritch V, Jaakola V-P, Lane JR, et al. Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists. J Med Chem 2010; 53(4): 1799-809.
[45]
van der Horst E, van der Pijl R, Mulder-Krieger T, Bender A, Ijzerman AP. Substructure-based virtual screening for adenosine A2A receptor ligands. ChemMedChem 2011; 6(12): 2302-11.
[46]
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.
[47]
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.
[48]
Langmead CJ, Andrews SP, Congreve M, et al. Identification of novel adenosine A(2A) receptor antagonists by virtual screening. J Med Chem 2012; 55(5): 1904-9.
[49]
Chen D, Ranganathan A, IJzerman AP, Siegal G, Carlsson J. Complementarity between in silico and biophysical screening approaches in fragment-based lead discovery against the A(2A) adenosine receptor. J Chem Inf Model 2013; 53(10): 2701-14.
[50]
Rodríguez D, Gao Z-G, Moss SM, Jacobson KA, Carlsson J. Molecular docking screening using agonist-bound GPCR structures: probing the A2A adenosine receptor. J Chem Inf Model 2015; 55(3): 550-63.
[51]
Ranganathan A, Stoddart LA, Hill SJ, Carlsson J. Fragment-Based Discovery of Subtype-Selective Adenosine Receptor Ligands from Homology Models. J Med Chem 2015; 58(24): 9578-90.
[52]
Lenselink EB, Beuming T, van Veen C, et al. In search of novel ligands using a structure-based approach: A case study on the adenosine A2A receptor. J Comput Aided Mol Des 2016; 30(10): 863-74.
[53]
Tian S, Wang X, Li L, et al. Discovery of Novel and Selective Adenosine A2A Receptor Antagonists for Treating Parkinson’s Disease through Comparative Structure-Based Virtual Screening. J Chem Inf Model 2017; 57(6): 1474-87.
[54]
Johnston JM, Filizola M. Showcasing modern molecular dynamics simulations of membrane proteins through G protein-coupled receptors. Curr Opin Struct Biol 2011; 21(4): 552-8.
[55]
Tarcsay A, Paragi G, Vass M, Jójárt B, Bogár F, Keserű GM. The impact of molecular dynamics sampling on the performance of virtual screening against GPCRs. J Chem Inf Model 2013; 53(11): 2990-9.
[56]
Ng HW, Laughton CA, Doughty SW. Molecular dynamics simulations of the adenosine A2a receptor: structural stability, sampling, and convergence. J Chem Inf Model 2013; 53(5): 1168-78.
[57]
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.
[58]
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.
[59]
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.
[60]
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.
[61]
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: 1081-5.
[62]
Dror RO, Green HF, Valant C, et al. Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 2013; 503(7475): 295-9.
[63]
Dror RO, Pan AC, Arlow DH, et al. Pathway and mechanism of drug binding to G-protein-coupled receptors. Proc Natl Acad Sci USA 2011; 108(32): 13118-23.
[64]
Kim S-K, Gao Z-G, Van Rompaey P, et al. Modeling the adenosine receptors: comparison of the binding domains of A2A agonists and antagonists. J Med Chem 2003; 46(23): 4847-59.
[65]
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.
[66]
Morizzo E, Capelli F, Lenzi O, et al. Scouting human A3 adenosine receptor antagonist binding mode using a molecular simplification approach: from triazoloquinoxaline to a pyrimidine skeleton as a key study. J Med Chem 2007; 50(26): 6596-606.
[67]
Ye Y, Wei J, Dai X, Gao Q. Computational studies of the binding modes of A 2A adenosine receptor antagonists. Amino Acids 2008; 35(2): 389-96.
[68]
Colotta V, Lenzi O, Catarzi D, et al. Pyrido [2,3-e]-1,2,4-triazolo [4,3-a]pyrazin-1-one as a new scaffold to develop potent and selective human A3 adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand-receptor modeling studies. J Med Chem 2009; 52(8): 2407-19.
[69]
Liu Y, Burger SK, Ayers PW, Vöhringer-Martinez E. Computational study of the binding modes of caffeine to the adenosine A2A receptor. J Phys Chem B 2011; 115(47): 13880-90.
[70]
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.
[71]
Xia L, Burger WAC, van Veldhoven JPD, et al. Structure-Affinity Relationships and Structure-Kinetics Relationships of Pyrido [2,1-f]purine-2,4-dione Derivatives as Human Adenosine A3 Receptor Antagonists. J Med Chem 2017; 60(17): 7555-68.
[72]
Lagarias P, Vrontaki E, Lambrinidis G, et al. Discovery of Novel Adenosine Receptor Antagonists through a Combined Structure- and Ligand-Based Approach Followed by Molecular Dynamics Investigation of Ligand Binding Mode. J Chem Inf Model 2018; 58(4): 794-815.
[73]
Tafi A, Bernardini C, Botta M, et al. Pharmacophore based receptor modeling: the case of adenosine A3 receptor antagonists. An approach to the optimization of protein models. J Med Chem 2006; 49(14): 4085-97.
[74]
Wei J, Wang S, Gao S, Dai X, Gao Q. 3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists. J Chem Inf Model 2007; 47(2): 613-25.
[75]
Michielan L, Bacilieri M, Schiesaro A, et al. Linear and nonlinear 3D-QSAR approaches in tandem with ligand-based homology modeling as a computational strategy to depict the pyrazolo-triazolo-pyrimidine antagonists binding site of the human adenosine A2A receptor. J Chem Inf Model 2008; 48(2): 350-63.
[76]
Almerico AM, Tutone M, Pantano L, Lauria A. A3 adenosine receptor: homology modeling and 3D-QSAR studies. J Mol Graph Model 2013; 42: 60-72.
[77]
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.
[78]
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.
[79]
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.
[80]
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.

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