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Mini-Reviews in Medicinal Chemistry


ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Transforming Non-Selective Angiotensin-Converting Enzyme Inhibitors in C- and N-domain Selective Inhibitors by Using Computational Tools

Author(s): Sergio Alfaro, Carlos Navarro-Retamal and Julio Caballero*

Volume 20, Issue 14, 2020

Page: [1436 - 1446] Pages: 11

DOI: 10.2174/1389557520666191224113830

Price: $65


The two-domain dipeptidylcarboxypeptidase Angiotensin-I-converting enzyme (EC; ACE) plays an important physiological role in blood pressure regulation via the reninangiotensin and kallikrein-kinin systems by converting angiotensin I to the potent vasoconstrictor angiotensin II, and by cleaving a number of other substrates including the vasodilator bradykinin and the anti-inflammatory peptide N-acetyl-SDKP. Therefore, the design of ACE inhibitors is within the priorities of modern medical sciences for treating hypertension, heart failures, myocardial infarction, and other related diseases. Despite the success of ACE inhibitors for the treatment of hypertension and congestive heart failure, they have some adverse effects, which could be attenuated by selective domain inhibition. Crystal structures of both ACE domains (nACE and cACE) reported over the last decades could facilitate the rational drug design of selective inhibitors. In this review, we refer to the history of the discovery of ACE inhibitors, which has been strongly related to the development of molecular modeling methods. We stated that the design of novel selective ACE inhibitors is a challenge for current researchers which requires a thorough understanding of the structure of both ACE domains and the help of molecular modeling methodologies. Finally, we performed a theoretical design of potential selective derivatives of trandolaprilat, a drug approved to treat critical conditions of hypertension, to illustrate how to use molecular modeling methods such as de novo design, docking, Molecular Dynamics (MD) simulations, and free energy calculations for creating novel potential drugs with specific interactions inside nACE and cACE binding sites.

Keywords: Selective angiotensin-converting enzyme (ACE) inhibitors, docking, molecular dynamics, de novo design, MM/GBSA, myocardial infarction.

Graphical Abstract
Soffer, R.L. Angiotensin-converting enzyme and the regulation of vasoactive peptides. Annu. Rev. Biochem., 1976, 45, 73-94.
[] [PMID: 183603]
Tamargo, M.; Tamargo, J. Future drug discovery in renin-angiotensin-aldosterone system intervention. Expert Opin. Drug Discov., 2017, 12(8), 827-848.
[] [PMID: 28541811]
Williams, B. Drug discovery in renin-angiotensin system intervention: Past and future. Ther. Adv. Cardiovasc. Dis., 2016, 10(3), 118-125.
[] [PMID: 27126389]
Mirabito Colafella, K.M.; Bovée, D.M.; Danser, A.H.J. The reninangiotensin- aldosterone system and its therapeutic targets. Exp. Eye Res., 2019., 186107680.
[] [PMID: 31129252]
Ng, K.K.; Vane, J.R. Conversion of angiotensin I to angiotensin II. Nature, 1967, 216(5117), 762-766.
[] [PMID: 4294626]
Ng, K.K.; Vane, J.R. Fate of angiotensin I in the circulation. Nature, 1968, 218(5137), 144-150.
[] [PMID: 4296306]
Ferreira, S.H.; Greene, L.H.; Alabaster, V.A.; Bakhle, Y.S.; Vane, J.R. Activity of various fractions of bradykinin potentiating factor against angiotensin I converting enzyme. Nature, 1970, 225(5230), 379-380.
[] [PMID: 4312128]
Yang, H.Y.; Erdös, E.G.; Levin, Y. A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim. Biophys. Acta, 1970, 214(2), 374-376.
[] [PMID: 4322742]
Ferreira, S.H. A Bradykinin-Potentiating Factor (Bpf) present in the venom of bothrops jararaca. Br. J. Pharmacol. Chemother., 1965, 24, 163-169.
[] [PMID: 14302350]
Bakhle, Y.S. Conversion of angiotensin I to angiotensin II by cell free extracts of dog lung. Nature, 1968, 220(5170), 919-921.
[] [PMID: 4301850]
Ferreira, S.H.; Bartelt, D.C.; Greene, L.J. Isolation of bradykinin potentiating peptides from Bothrops jararaca venom. Biochemistry, 1970, 9(13), 2583-2593.
[] [PMID: 4317874]
Cushman, D.W.; Pluscec, J.; Williams, N.J.; Weaver, E.R.; Sabo, E.F.; Kocy, O.; Cheung, H.S.; Ondetti, M.A. Inhibition of angiotensin-coverting enzyme by analogs of peptides from Bothrops jararaca venom. Experientia, 1973, 29(8), 1032-1035.
[] [PMID: 4354751]
Ondetti, M.A.; Rubin, B.; Cushman, D.W. Design of specific inhibitors of angiotensin-converting enzyme: New class of orally active antihypertensive agents. Science, 1977, 196(4288), 441-444.
[] [PMID: 191908]
Cushman, D.W.; Cheung, H.S.; Sabo, E.F.; Ondetti, M.A. Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry, 1977, 16(25), 5484-5491.
[] [PMID: 200262]
Opie, L.H.; Kowolik, H. The discovery of captopril: From large animals to small molecules. Cardiovasc. Res., 1995, 30(1), 18-25.
[] [PMID: 7553719]
Ulm, E.H.; Hichens, M.; Gomez, H.J.; Till, A.E.; Hand, E.; Vassil, T.C.; Biollaz, J.; Brunner, H.R.; Schelling, J.L. Enalapril maleate and a lysine analogue (MK-521): Disposition in man. Br. J. Clin. Pharmacol., 1982, 14(3), 357-362.
[] [PMID: 6289858]
Song, J.C.; White, C.M. Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: An update. Clin. Pharmacokinet., 2002, 41(3), 207-224.
[] [PMID: 11929321]
Nathisuwan, S.; Talbert, R.L. A review of vasopeptidase inhibitors: A new modality in the treatment of hypertension and chronic heart failure. Pharmacotherapy, 2002, 22(1), 27-42.
[] [PMID: 11794428]
Nussberger, J.; Cugno, M.; Amstutz, C.; Cicardi, M.; Pellacani, A.; Agostoni, A. Plasma bradykinin in angio-oedema. Lancet, 1998, 351(9117), 1693-1697.
[] [PMID: 9734886]
Bernstein, K.E.; Ong, F.S.; Blackwell, W-L.B.; Shah, K.H.; Giani, J.F.; Gonzalez-Villalobos, R.A.; Shen, X.Z.; Fuchs, S.; Touyz, R.M. A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme. Pharmacol. Rev., 2012, 65(1), 1-46.
[] [PMID: 23257181]
Fuchs, S.; Xiao, H.D.; Hubert, C.; Michaud, A.; Campbell, D.J.; Adams, J.W.; Capecchi, M.R.; Corvol, P.; Bernstein, K.E. Angiotensin-converting enzyme C-terminal catalytic domain is the main site of angiotensin I cleavage in vivo. Hypertension, 2008, 51(2), 267-274.
[] [PMID: 18158355]
Kumar, N.; Yin, C. The anti-inflammatory peptide Ac-SDKP: Synthesis, role in ACE inhibition, and its therapeutic potential in hypertension and cardiovascular diseases. Pharmacol. Res., 2018, 134, 268-279.
[] [PMID: 29990624]
Bernstein, K.E.; Shen, X.Z.; Gonzalez-Villalobos, R.A.; Billet, S.; Okwan-Duodu, D.; Ong, F.S.; Fuchs, S. Different in vivo functions of the two catalytic domains of angiotensin-converting enzyme (ACE). Curr. Opin. Pharmacol., 2011, 11(2), 105-111.
[] [PMID: 21130035]
Messerli, F.H.; Nussberger, J. Vasopeptidase inhibition and angio-oedema. Lancet, 2000, 356(9230), 608-609.
[] [PMID: 10968427]
Cotton, J.; Hayashi, M.A.F.; Cuniasse, P.; Vazeux, G.; Ianzer, D.; De Camargo, A.C.M.; Dive, V. Selective inhibition of the C domain of angiotensin I converting enzyme by bradykinin potentiating peptides. Biochemistry, 2002, 41(19), 6065-6071.
[] [PMID: 11994001]
Bonnet, D.; Lemoine, F.M.; Khoury, E.; Pradelles, P.; Najman, A.; Guigon, M. Reversible inhibitory effects and absence of toxicity of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in human long-term bone marrow culture. Exp. Hematol., 1992, 20(10), 1165-1169.
[PMID: 1385195]
Sharma, U.; Rhaleb, N-E.; Pokharel, S.; Harding, P.; Rasoul, S.; Peng, H.; Carretero, O.A. Novel anti-inflammatory mechanisms of N-Acetyl-Ser-Asp-Lys-Pro in hypertension-induced target organ damage. Am. J. Physiol. Heart Circ. Physiol., 2008, 294(3), H1226-H1232.
[] [PMID: 18178715]
Castoldi, G.; di Gioia, C.R.T.; Bombardi, C.; Perego, C.; Perego, L.; Mancini, M.; Leopizzi, M.; Corradi, B.; Perlini, S.; Zerbini, G.; Stella, A. Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats. Clin. Sci. (Lond.), 2009, 118(3), 211-220.
[] [PMID: 20310083]
Liu, Y-H.; D’Ambrosio, M.; Liao, T.D.; Peng, H.; Rhaleb, N-E.; Sharma, U.; André, S.; Gabius, H-J.; Carretero, O.A. N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth regulatory lectin. Am. J. Physiol. Heart Circ. Physiol., 2009, 296(2), H404-H412.
[] [PMID: 19098114]
Peng, H.; Carretero, O.A.; Liao, T-D.; Peterson, E.L.; Rhaleb, N-E. Role of N-acetyl-seryl-aspartyl-lysyl-proline in the antifibrotic and anti-inflammatory effects of the angiotensin-converting enzyme inhibitor captopril in hypertension. Hypertension, 2007, 49(3), 695-703.
[] [PMID: 17283252]
Fuchs, S.; Xiao, H.D.; Cole, J.M.; Adams, J.W.; Frenzel, K.; Michaud, A.; Zhao, H.; Keshelava, G.; Capecchi, M.R.; Corvol, P.; Bernstein, K.E. Role of the N-terminal catalytic domain of angiotensin-converting enzyme investigated by targeted inactivation in mice. J. Biol. Chem., 2004, 279(16), 15946-15953.
[] [PMID: 14757757]
Acharya, K.R.; Sturrock, E.D.; Riordan, J.F.; Ehlers, M.R.W. Ace revisited: A new target for structure-based drug design. Nat. Rev. Drug Discov., 2003, 2(11), 891-902.
[] [PMID: 14668810]
Dive, V.; Cotton, J.; Yiotakis, A.; Michaud, A.; Vassiliou, S.; Jiracek, J.; Vazeux, G.; Chauvet, M.T.; Cuniasse, P.; Corvol, P. RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites. Proc. Natl. Acad. Sci. USA, 1999, 96(8), 4330-4335.
[] [PMID: 10200262]
Georgiadis, D.; Cuniasse, P.; Cotton, J.; Yiotakis, A.; Dive, V. Structural determinants of RXPA380, a potent and highly selective inhibitor of the angiotensin-converting enzyme C-domain. Biochemistry, 2004, 43(25), 8048-8054.
[] [PMID: 15209500]
Anthony, C.S.; Corradi, H.R.; Schwager, S.L.U.; Redelinghuys, P.; Georgiadis, D.; Dive, V.; Acharya, K.R.; Sturrock, E.D. The N domain of human angiotensin-I-converting enzyme: The role of N-glycosylation and the crystal structure in complex with an N domain-specific phosphinic inhibitor, RXP407. J. Biol. Chem., 2010, 285(46), 35685-35693.
[] [PMID: 20826823]
Natesh, R.; Schwager, S.L.U.; Sturrock, E.D.; Acharya, K.R. Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature, 2003, 421(6922), 551-554.
[] [PMID: 12540854]
Natesh, R.; Schwager, S.L.U.; Evans, H.R.; Sturrock, E.D.; Acharya, K.R. Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I converting enzyme. Biochemistry, 2004, 43(27), 8718-8724.
[] [PMID: 15236580]
Corradi, H.R.; Schwager, S.L.U.; Nchinda, A.T.; Sturrock, E.D.; Acharya, K.R. Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design. J. Mol. Biol., 2006, 357(3), 964-974.
[] [PMID: 16476442]
Brew, K. Structure of human ACE gives new insights into inhibitor binding and design. Trends Pharmacol. Sci., 2003, 24(8), 391-394.
[] [PMID: 12915047]
Kuster, D.J.; Marshall, G.R. Validated ligand mapping of ACE active site. J. Comput. Aided Mol. Des., 2005, 19(8), 609-615.
[] [PMID: 16307311]
Rao, N.K.; Yadav, A.; Kumar Singh, S. An ab initio quantum mechanical drug designing procedure: Application to the design of balanced dual ACE/NEP inhibitors. J. Mol. Model., 2009, 15(12), 1447-1462.
[] [PMID: 19430822]
Dimitropoulos, N.; Papakyriakou, A.; Dalkas, G.A.; Sturrock, E.D.; Spyroulias, G.A. A computational approach to the study of the binding mode of dual ACE/NEP inhibitors. J. Chem. Inf. Model., 2010, 50(3), 388-396.
[] [PMID: 20170101]
Wang, X.; Wang, J.; Lin, Y.; Ding, Y.; Wang, Y.; Cheng, X.; Lin, Z. QSAR study on angiotensin-converting enzyme inhibitor oligopeptides based on a novel set of sequence information descriptors. J. Mol. Model., 2011, 17(7), 1599-1606.
[] [PMID: 20941517]
Wang, X.; Wu, S.; Xu, D.; Xie, D.; Guo, H. Inhibitor and substrate binding by angiotensin-converting enzyme: Quantum mechanical/molecular mechanical molecular dynamics studies. J. Chem. Inf. Model., 2011, 51(5), 1074-1082.
[] [PMID: 21520937]
Hai-Bang, T.; Shimizu, K. Potent angiotensin-converting enzyme inhibitory tripeptides identified by a computer-based approach. J. Mol. Graph. Model., 2014, 53, 206-211.
[] [PMID: 25181455]
Ke, Z.; Su, Z.; Zhang, X.; Cao, Z.; Ding, Y.; Cao, L.; Ding, G.; Wang, Z.; Liu, H.; Xiao, W. Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening. Bioorg. Med. Chem. Lett., 2017, 27(16), 3688-3692.
[] [PMID: 28712707]
Panyayai, T.; Sangsawad, P.; Pacharawongsakda, E.; Sawatdichaikul, O.; Tongsima, S.; Choowongkomon, K. The potential peptides against angiotensin-I converting enzyme through a virtual tripeptide-constructing library. Comput. Biol. Chem., 2018, 77, 207-213.
[] [PMID: 30347317]
Douglas, R.G.; Sharma, R.K.; Masuyer, G.; Lubbe, L.; Zamora, I.; Acharya, K.R.; Chibale, K.; Sturrock, E.D. Fragment-based design for the development of N-domain-selective angiotensin-1-converting enzyme inhibitors. Clin. Sci. (Lond.), 2014, 126(4), 305-313.
[] [PMID: 24015848]
Bergmann, R.; Linusson, A.; Zamora, I. SHOP: Scaffold HOPping by GRID-based similarity searches. J. Med. Chem., 2007, 50(11), 2708-2717.
[] [PMID: 17489578]
Bergmann, R.; Liljefors, T.; Sørensen, M.D.; Zamora, I. SHOP: Receptor-based scaffold HOPping by GRID-based similarity searches. J. Chem. Inf. Model., 2009, 49(3), 658-669.
[] [PMID: 19265417]
Fienberg, S.; Cozier, G.E.; Acharya, K.R.; Chibale, K.; Sturrock, E.D. The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme. J. Med. Chem., 2018, 61(1), 344-359.
[] [PMID: 29206036]
GOSTAR Drug Database and Clinical Candidate Database; Excelra Knowledge Solutions: Hyderabad, India, Jul 22, 2013.
Wallis, E.J.; Ramsay, L.E.; Hettiarachchi, J. Combined inhibition of neutral endopeptidase and angiotensin-converting enzyme by sampatrilat in essential hypertension. Clin. Pharmacol. Ther., 1998, 64(4), 439-449.
[] [PMID: 9797801]
Venn, R.F.; Kaye, B.; Macrae, P.V.; Saunders, K.C. Clinical analysis of sampatrilat, a combined renal endopeptidase and angiotensin-converting enzyme inhibitor I: Assay in plasma of human volunteers by atmospheric-pressure ionisation mass-spectrometry following derivatisation with BF3-methanol. J. Pharm. Biomed. Anal., 1998, 16(5), 875-881.
[] [PMID: 9535199]
Venn, R.F.; Barnard, G.; Kaye, B.; Macrae, P.V.; Saunders, K.C. Clinical analysis of sampatrilat, a combined renal endopeptidase and angiotensin-converting enzyme inhibitor II: Assay in the plasma and urine of human volunteers by dissociation enhanced lanthanide fluorescence immunoassay (DELFIA). J. Pharm. Biomed. Anal., 1998, 16(5), 883-892.
[] [PMID: 9535200]
Sharma, R.K.; Espinoza-Moraga, M.; Poblete, H.; Douglas, R.G.; Sturrock, E.D.; Caballero, J.; Chibale, K. The Dynamic Nonprime Binding of Sampatrilat to the C-Domain of Angiotensin-Converting Enzyme. J. Chem. Inf. Model., 2016, 56(12), 2486-2494.
[] [PMID: 27959521]
Cozier, G.E.; Schwager, S.L.; Sharma, R.K.; Chibale, K.; Sturrock, E.D.; Acharya, K.R. Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity. FEBS J., 2018, 285(8), 1477-1490.
[] [PMID: 29476645]
Guay, D.R.P. Trandolapril: A newer angiotensin-converting enzyme inhibitor. Clin. Ther., 2003, 25(3), 713-775.
[] [PMID: 12852701]
Wiseman, L.R.; McTavish, D. Trandolapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs, 1994, 48(1), 71-90.
[] [PMID: 7525196]
Conen, H.; Brunner, H.R. Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor. Am. Heart J., 1993, 125(5 Pt 2), 1525-1531.
[] [PMID: 8480624]
Tytus, R.H.; Burgess, E.D.; Assouline, L.; Vanjaka, A. A 26-week, prospective, open-label, uncontrolled, multicenter study to evaluate the effect of an escalating-dose regimen of trandolapril on change in blood pressure in treatment-naive and concurrently treated adult hypertensive subjects (TRAIL). Clin. Ther., 2007, 29(2), 305-315.
[] [PMID: 17472822]
Pierce, A.C.; Rao, G.; Bemis, G.W. BREED: Generating novel inhibitors through hybridization of known ligands. Application to CDK2, p38, and HIV protease. J. Med. Chem., 2004, 47(11), 2768-2775.
[] [PMID: 15139755]
Ho, C.M.W.; Marshall, G.R. SPLICE: A program to assemble partial query solutions from Three-Dimensional Database Searches into novel ligands. J. Comput. Aided Mol. Des., 1993, 7, 623-647.
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[] [PMID: 15027865]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[] [PMID: 17034125]
Fuentes, E.; Badimon, L.; Caballero, J.; Padró, T.; Vilahur, G.; Alarcón, M.; Pérez, P.; Palomo, I. Protective mechanisms of adenosine 5′-monophosphate in platelet activation and thrombus formation. Thromb. Haemost., 2014, 111(3), 491-507.
[] [PMID: 24306059]
Fuentes, E.; Pereira, J.; Mezzano, D.; Alarcón, M.; Caballero, J.; Palomo, I. Inhibition of platelet activation and thrombus formation by adenosine and inosine: Studies on their relative contribution and molecular modeling. PLoS One, 2014, 9(11), e11274.
[] [PMID: 25393959]
Fuentes, E.; Caballero, J.; Alarcón, M.; Rojas, A.; Palomo, I. Chlorogenic acid inhibits human platelet activation and thrombus formation. PLoS One, 2014, 9(3), e90699.
[] [PMID: 24598787]
Quesada-Romero, L.; Mena-Ulecia, K.; Tiznado, W.; Caballero, J. Insights into the interactions between maleimide derivates and GSK3β combining molecular docking and QSAR. PLoS One, 2014, 9(7), e102212.
[] [PMID: 25010341]
Bowers, K.J.; Chow, E.; Xu, H.; Dror, R.O.; Eastwood, M.P.; Gregersen, B.A.; Klepeis, J.L.; Kolossvary, I.; Moraes, M.A.; Sacerdoti, F.D.; Salmon, J.K.; Shan, Y.; Shaw, D.E. Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters Proceedings of the Proceedings of the 2006 ACM/IEEE conference on Supercomputing., 2006, 84
Kaminski, G.A.; Friesner, R.A.; Tirado-Rives, J.; Jorgensen, W.L. Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. J. Phys. Chem. B, 2001, 105, 6474-6487.
Adasme-Carreño, F.; Muñoz-Gutierrez, C.; Caballero, J.; Alzate-Morales, J.H. Performance of the MM/GBSA scoring using a binding site hydrogen bond network-based frame selection: The protein kinase case. Phys. Chem. Chem. Phys., 2014, 16(27), 14047-14058.
[] [PMID: 24901037]
Lee, M.R.; Sun, Y. Improving docking accuracy through molecular mechanics generalized born optimization and scoring. J. Chem. Theory Comput., 2007, 3(3), 1106-1119.
[] [PMID: 26627430]
Mena-Ulecia, K.; Vergara-Jaque, A.; Poblete, H.; Tiznado, W.; Caballero, J. Study of the affinity between the protein kinase PKA and peptide substrates derived from kemptide using molecular dynamics simulations and MM/GBSA. PLoS One, 2014, 9(10), e109639.
[] [PMID: 25275314]
Ramírez, D.; Caballero, J. Is it reliable to use common molecular docking methods for comparing the binding affinities of enantiomer pairs for their protein target? Int. J. Mol. Sci., 2016, 17(4), 525.
[] [PMID: 27104528]

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