Abstract
Background: Hydroxychloroquine (HCQ) is a common antimalarial drug that has been used effectively in the treatment of various rheumatic and auto-immunity diseases. The major side effects and drawbacks associated with HCQ are cardiotoxicity, retinopathy, gastrointestinal upset, and neuromyopathy however, cardiotoxicity is an increasing concern and it is critical to avoid heart dysfunction induced by HCQ. The present work is focused on receptor and signaling molecules associated with pathways attributing to drug-induced cardiotoxicity. We analyzed the therapeutic efficacy of selected natural products in HCQ-induced cardiotoxicity through insilico. We selected Syzygium cumini polyphenols, quercetin, and p-coumaric acid. The motivation behind selecting quercetin, and p-coumaric acid is their wide applicability as an antioxidative, anti-inflammatory, antiapoptotic, and cardioprotective.
Methods: For predicting quercetin, p-coumaric acid, and HCQ toxicity and physicochemical properties, in silico studies were performed using ProTox II and Swiss ADME. We further performed molecular docking using Autodock Vina and Discovery Studio visualizer to find the affinity of selected polyphenols against signaling molecules and receptors. Then we performed network pharmacological studies of selected signaling molecules.
Results: We analyzed that the computational method indicated quercetin (Δ G -9.3 kcal/mol) has greater binding affinity than p-Coumaric acid for prevention and restoration of the disease while hydroxychloroquine was taken as a control.
Conclusion: It can be concluded that Syzygium cumini, polyphenols may aid in the future therapeutic potential against HCQ-induced cardiotoxicity.
Graphical Abstract
[1]
Dong J, Chen H. Cardiotoxicity of anticancer therapeutics. Cardiovasc Med 2018; 7: 5-9.
[http://dx.doi.org/10.3389/fcvm.2018.00009]
[http://dx.doi.org/10.3389/fcvm.2018.00009]
[2]
Xia P, Liu Y, Cheng Z. Signaling pathways in cardiac myocyte apoptosis. BioMed Res Int 2016; 2016: 1-22.
[http://dx.doi.org/10.1155/2016/9583268] [PMID: 28101515]
[http://dx.doi.org/10.1155/2016/9583268] [PMID: 28101515]
[3]
Lamore SD, Kohnken RA, Peters MF, Kolaja KL. Cardiovascular toxicity induced by kinase inhibitors: Mechanisms and preclinical approaches. Chem Res Toxicol 2020; 33(1): 125-36.
[http://dx.doi.org/10.1021/acs.chemrestox.9b00387] [PMID: 31840498]
[http://dx.doi.org/10.1021/acs.chemrestox.9b00387] [PMID: 31840498]
[4]
Fram G, Wang DD, Malette K, et al. Cardiac complications attributed to hydroxychloroquine: A systematic review of the literature pre-COVID-19. Curr Cardiol Rev 2021; 17(3): 319-27.
[http://dx.doi.org/10.2174/18756557MTEwtNjYpz] [PMID: 33059567]
[http://dx.doi.org/10.2174/18756557MTEwtNjYpz] [PMID: 33059567]
[5]
Al-Bari MAA. Chloroquine analogues in drug discovery: New directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother 2015; 70(6): 1608-21.
[http://dx.doi.org/10.1093/jac/dkv018] [PMID: 25693996]
[http://dx.doi.org/10.1093/jac/dkv018] [PMID: 25693996]
[6]
Seydi E, Hassani MK, Naderpour S, Arjmand A, Pourahmad J. Cardiotoxicity of chloroquine and hydroxychloroquine through mitochondrial pathway. BMC Pharmacol Toxicol 2023; 24(1): 26.
[http://dx.doi.org/10.1186/s40360-023-00666-x] [PMID: 37085872]
[http://dx.doi.org/10.1186/s40360-023-00666-x] [PMID: 37085872]
[7]
Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine: A systematic review of the literature. Drug Saf 2018; 41(10): 919-31.
[http://dx.doi.org/10.1007/s40264-018-0689-4] [PMID: 29858838]
[http://dx.doi.org/10.1007/s40264-018-0689-4] [PMID: 29858838]
[8]
Zhao H, Wald J, Palmer M, Han Y. Hydroxychloroquine-induced cardiomyopathy and heart failure in twins. J Thorac Dis 2018; 10(1): E70-3.
[http://dx.doi.org/10.21037/jtd.2017.12.66] [PMID: 29600108]
[http://dx.doi.org/10.21037/jtd.2017.12.66] [PMID: 29600108]
[9]
Yogasundaram H, Putko BN, Tien J, et al. Hydroxychloroquine-induced cardiomyopathy: Case report, pathophysiology, diagnosis, and treatment. Can J Cardiol 2014; 30(12): 1706-15.
[http://dx.doi.org/10.1016/j.cjca.2014.08.016] [PMID: 25475472]
[http://dx.doi.org/10.1016/j.cjca.2014.08.016] [PMID: 25475472]
[10]
Bonam SR, Wang F, Muller S. Lysosomes as a therapeutic target. Nat Rev Drug Discov 2019; 18(12): 923-48.
[http://dx.doi.org/10.1038/s41573-019-0036-1] [PMID: 31477883]
[http://dx.doi.org/10.1038/s41573-019-0036-1] [PMID: 31477883]
[11]
Sperber K, Quraishi H, Kalb TH, Panja A, Stecher V, Mayer L. Selective regulation of cytokine secretion by hydroxychloroquine: Inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol 1993; 20(5): 803-8.
[PMID: 8336306]
[PMID: 8336306]
[12]
Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology. Nat Rev Rheumatol 2020; 16(3): 155-66.
[http://dx.doi.org/10.1038/s41584-020-0372-x] [PMID: 32034323]
[http://dx.doi.org/10.1038/s41584-020-0372-x] [PMID: 32034323]
[13]
An P, Wan S, Luo Y, et al. Micronutrient supplementation to reduce cardiovascular risk. J Am Coll Cardiol 2022; 80(24): 2269-85.
[http://dx.doi.org/10.1016/j.jacc.2022.09.048] [PMID: 36480969]
[http://dx.doi.org/10.1016/j.jacc.2022.09.048] [PMID: 36480969]
[14]
Gormaz JG, Carrasco R. Antioxidant supplementation in cardiovascular prevention. J Am Coll Cardiol 2022; 80(24): 2286-8.
[http://dx.doi.org/10.1016/j.jacc.2022.10.011] [PMID: 36480970]
[http://dx.doi.org/10.1016/j.jacc.2022.10.011] [PMID: 36480970]
[15]
Singh S, Agarwal N. Study the pharmacognostic profile, antiradical and hepatoprotective potential of carissacarandas linn. fruit extract. Recent Pat Food Nutr Agric 2022; 2.
[PMID: 35236277]
[PMID: 35236277]
[16]
Atale N, Mishra CB, Kohli S, et al. Anti-inflammatory effects of s. cumini seed extract on gelatinase-b (mmp-9) regulation against hyperglycemic cardiomyocyte stress. Oxid Med Cell Longev 2021; 2021: 1-14.
[http://dx.doi.org/10.1155/2021/8839479] [PMID: 33747350]
[http://dx.doi.org/10.1155/2021/8839479] [PMID: 33747350]
[17]
Dong Q, Chen L, Lu Q, et al. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression. Br J Pharmacol 2014; 171(19): 4440-54.
[http://dx.doi.org/10.1111/bph.12795] [PMID: 24902966]
[http://dx.doi.org/10.1111/bph.12795] [PMID: 24902966]
[18]
Sunitha MC, Dhanyakrishnan R, PrakashKumar B, Nevin KG. p-Coumaric acid mediated protection of H9c2 cells from Doxorubicin-induced cardiotoxicity: Involvement of augmented Nrf2 and autophagy. Biomed Pharmacother 2018; 102: 823-32.
[http://dx.doi.org/10.1016/j.biopha.2018.03.089] [PMID: 29605770]
[http://dx.doi.org/10.1016/j.biopha.2018.03.089] [PMID: 29605770]
[19]
Naveed M, Majeed F, Taleb A, et al. A review of medicinal plants in cardiovascular disorders: Benefits and risks. Am J Chin Med 2020; 48(2): 259-86.
[http://dx.doi.org/10.1142/S0192415X20500147] [PMID: 32345058]
[http://dx.doi.org/10.1142/S0192415X20500147] [PMID: 32345058]
[20]
Costanzo LD, Ghosh S, Zardecki C, Burley SK. Using the tools and resources of theRCSB protein data bank Curr Protoc Bioinformatics 2016; 55: 1.9.1–1.9.35.
[21]
Laskowski RA, Thornton JM. PDBsum extras: SARS‐CoV ‐2 and AlphaFold models. Protein Sci 2022; 31(1): 283-9.
[http://dx.doi.org/10.1002/pro.4238] [PMID: 34779073]
[http://dx.doi.org/10.1002/pro.4238] [PMID: 34779073]
[22]
Lipinski CA. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov Today Technol 2004; 1(4): 337-41.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[23]
Chen X, Li H, Tian L, Li Q, Luo J, Zhang Y. Analysis of the physicochemical properties of acaricides based on lipinski’s rule of five. J Comput Biol 2020; 27(9): 1397-406.
[http://dx.doi.org/10.1089/cmb.2019.0323] [PMID: 32031890]
[http://dx.doi.org/10.1089/cmb.2019.0323] [PMID: 32031890]
[24]
Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: Protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res 2015; 43(D1): D447-52.
[http://dx.doi.org/10.1093/nar/gku1003] [PMID: 25352553]
[http://dx.doi.org/10.1093/nar/gku1003] [PMID: 25352553]
[25]
Li J, Fu A, Zhang L. An overview of scoring functions used for protein–ligand interactions in molecular docking. Interdiscip Sci 2019; 11(2): 320-8.
[http://dx.doi.org/10.1007/s12539-019-00327-w] [PMID: 30877639]
[http://dx.doi.org/10.1007/s12539-019-00327-w] [PMID: 30877639]
[26]
Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 2018; 46(W1): W257-63.
[http://dx.doi.org/10.1093/nar/gky318] [PMID: 29718510]
[http://dx.doi.org/10.1093/nar/gky318] [PMID: 29718510]
[27]
Drwal MN, Banerjee P, Dunkel M, Wettig MR, Preissner R. ProTox: A web server for the in silico prediction of rodent oral toxicity. Nucleic Acids Res 2014; 42: W53-8.
[http://dx.doi.org/10.1093/nar/gku401]
[http://dx.doi.org/10.1093/nar/gku401]
[28]
Banerjee P, Ulker OC. Combinative ex vivo studies and in silico models ProTox-II for investigating the toxicity of chemicals used mainly in cosmetic products. Toxicol Mech Methods 2022; 32(7): 542-8.
[http://dx.doi.org/10.1080/15376516.2022.2053623] [PMID: 35287538]
[http://dx.doi.org/10.1080/15376516.2022.2053623] [PMID: 35287538]
[29]
Daina A, Zoete V. A boiled-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem 2016; 11(11): 1117-21.
[http://dx.doi.org/10.1002/cmdc.201600182] [PMID: 27218427]
[http://dx.doi.org/10.1002/cmdc.201600182] [PMID: 27218427]
[30]
Daina A, Michielin O, Zoete V. Swisstargetprediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47(W1): W357-64.
[http://dx.doi.org/10.1093/nar/gkz382] [PMID: 31106366]
[http://dx.doi.org/10.1093/nar/gkz382] [PMID: 31106366]
[31]
Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49(D1): D605-12.
[http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]
[http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]
[32]
Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: New perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 2017; 45(D1): D353-61.
[http://dx.doi.org/10.1093/nar/gkw1092] [PMID: 27899662]
[http://dx.doi.org/10.1093/nar/gkw1092] [PMID: 27899662]
[33]
Cunningham P, Patton E, VanderVeen BN, et al. Sub-chronic oral toxicity screening of quercetin in mice. BMC Complem MedThera 2022; 22(1): 279.
[http://dx.doi.org/10.1186/s12906-022-03758-z] [PMID: 36274141]
[http://dx.doi.org/10.1186/s12906-022-03758-z] [PMID: 36274141]
[34]
Ge J, Shelby SL, Wang Y, et al. Cardioprotective properties of quercetin in fescue toxicosis-induced cardiotoxicity via heart-gut axis in lambs (Ovis Aries). J Hazard Mater 2023; 458: 131843.
[http://dx.doi.org/10.1016/j.jhazmat.2023.131843] [PMID: 37379607]
[http://dx.doi.org/10.1016/j.jhazmat.2023.131843] [PMID: 37379607]
[35]
Aziz TA. Cardioprotective effect of quercetin and sitagliptin in doxorubicin-induced cardiac toxicity in rats. Cancer Manag Res 2021; 13: 2349-57.
[http://dx.doi.org/10.2147/CMAR.S300495] [PMID: 33737832]
[http://dx.doi.org/10.2147/CMAR.S300495] [PMID: 33737832]
[36]
Chacko SM, Nevin KG, Dhanyakrishnan R, Kumar BP. Protective effect of p -coumaric acid against doxorubicin induced toxicity in H9c2 cardiomyoblast cell lines. Toxicol Rep 2015; 2: 1213-21.
[http://dx.doi.org/10.1016/j.toxrep.2015.08.002] [PMID: 28962464]
[http://dx.doi.org/10.1016/j.toxrep.2015.08.002] [PMID: 28962464]
[37]
Bories MC, Gibault L, Tharaux PL, Bruneval P. Toxic hydroxychloroquine-induced cardiomyopathy complicating systemic lupus treatment. Ann Pathol 2021; 41(1): 101-4.
[http://dx.doi.org/10.1016/j.annpat.2020.09.007] [PMID: 33419598]
[http://dx.doi.org/10.1016/j.annpat.2020.09.007] [PMID: 33419598]
[38]
Wille F, Birkmeier S, Tiemann K, et al. Proximal myopathy and fulminant heart failure in a 57 year-old female patient with lupus erythematosus. Internist 2020; 61(8): 854-9.
[http://dx.doi.org/10.1007/s00108-020-00820-1] [PMID: 32504300]
[http://dx.doi.org/10.1007/s00108-020-00820-1] [PMID: 32504300]
[39]
Chang A, Stolin G, Fan J, et al. Hypertrophic cardiomyopathy in a lupus patient: A case of hydroxychloroquine cardiotoxicity. ESC Heart Fail 2019; 6(6): 1326-30.
[http://dx.doi.org/10.1002/ehf2.12508] [PMID: 31493341]
[http://dx.doi.org/10.1002/ehf2.12508] [PMID: 31493341]
[40]
Tiwari S, Pandey VP, Yadav K, Dwivedi UN. Modulation of interaction of BRCA1-RAD51 and BRCA1-AURKA protein complexes by natural metabolites using as possible therapeutic intervention toward cardiotoxic effects of cancer drugs: An in-silico approach. J Biomol Struct Dyn 2022; 40(23): 12863-79.
[http://dx.doi.org/10.1080/07391102.2021.1976278] [PMID: 34632941]
[http://dx.doi.org/10.1080/07391102.2021.1976278] [PMID: 34632941]
[41]
Murad HAS, Alqurashi TMA, Hussien MA. Interactions of selected cardiovascular active natural compounds with CXCR4 and CXCR7 receptors: A molecular docking, molecular dynamics, and pharmacokinetic/toxicity prediction study. BMC Comple Med Therap 2022; 22(1): 35.
[http://dx.doi.org/10.1186/s12906-021-03488-8] [PMID: 35120520]
[http://dx.doi.org/10.1186/s12906-021-03488-8] [PMID: 35120520]
[42]
Syahputra RA, Harahap U, Dalimunthe A, Nasution MP, Satria D. The role of flavonoids as a cardioprotective strategy against doxorubicin-induced cardiotoxicity: A review. Molecules 2022; 27(4): 1320.
[http://dx.doi.org/10.3390/molecules27041320] [PMID: 35209107]
[http://dx.doi.org/10.3390/molecules27041320] [PMID: 35209107]
[43]
Reyes-Farias M, Carrasco-Pozo C. The anti-cancer effect of quercetin: Molecular implications in cancer metabolism. Int J Mol Sci 2019; 20(13): 3177.
[http://dx.doi.org/10.3390/ijms20133177] [PMID: 31261749]
[http://dx.doi.org/10.3390/ijms20133177] [PMID: 31261749]
[44]
Balakumar P, Jagadeesh G. Multifarious molecular signaling cascades of cardiac hypertrophy: Can the muddy waters be cleared? Pharmacol Res 2010; 62(5): 365-83.
[http://dx.doi.org/10.1016/j.phrs.2010.07.003] [PMID: 20643208]
[http://dx.doi.org/10.1016/j.phrs.2010.07.003] [PMID: 20643208]
[45]
Ramos-Kuri M, Meka SH, Salamanca-Buentello F, Hajjar RJ, Lipskaia L, Chemaly ER. Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies. Biol Res 2021; 54(1): 23.
[http://dx.doi.org/10.1186/s40659-021-00342-6] [PMID: 34344467]
[http://dx.doi.org/10.1186/s40659-021-00342-6] [PMID: 34344467]
[46]
Jindal D, Rani V. In Silico studies of phytoconstituents from piper longum and ocimum sanctum as ACE2 and TMRSS2 inhibitors: Strategies to combat COVID-19. Appl Biochem Biotechnol 2023; 195(4): 2618-35.
[http://dx.doi.org/10.1007/s12010-022-03827-6] [PMID: 35157239]
[http://dx.doi.org/10.1007/s12010-022-03827-6] [PMID: 35157239]
[47]
Singhal S, Rani V. Study to explore plant-derived trimethylamine lyase enzyme inhibitors to address gut dysbiosis. Appl Biochem Biotechnol 2022; 194(1): 99-123.
[http://dx.doi.org/10.1007/s12010-021-03747-x] [PMID: 34822060]
[http://dx.doi.org/10.1007/s12010-021-03747-x] [PMID: 34822060]
