Modelagem molecular de derivado do geniposídeo como inibidor da TMPRSS2 contra a COVID-19 / Molecular modeling of geniposide derivative as TMPRSS2 inhibitor Against COVID-19

Authors

  • Juliana de Araújo Ximenes
  • Ayumi Minori Rocha
  • Nilton Fabris Bezerra
  • Carlos Henrique Lamego Guimarães Thomaz Branco
  • Rhanna Victória Amaral da Silva
  • Fernanda Guilhon-Simplicio

DOI:

https://doi.org/10.34117/bjdv8n6-167

Keywords:

COVID-19, SARS-CoV-2, docking molecular, TMPRSS2.

Abstract

A COVID-19 tem sido um grave problema para saúde da população mundial e, embora apresente uma taxa de mortalidade de 2-3%, ocasionou milhares de mortes principalmente devido ao seu alto índice de transmissão (3 vezes maior que a SARS). O agente etiológico, um vírus denominado SARS-CoV-2, possui em sua membrana a glicoproteína Spike que para a efetivação da invasão, carece do auxílio da serina protease transmembranar do tipo II (TMPRSS2), presente na célula hospedeira. A TMPRSS2 é quem realiza clivagens proteolíticas na Enzima Conversora de Angiotensina (ACE2) e glicoproteína S. Com base nas evidências de que essa serina protease pode ser um alvo promissor, no presente estudo foi realizado uma proposta de molécula inibidora da TMPRSS2, como contribuição à investigação de tratamentos contra a COVID-19, usando como metodologia principal o docking molecular, que analisa a interação de uma micromolécula com resíduos de aminoácidos importantes na atividade catalítica da proteína-alvo, no caso His296, Ser441 e Asp345. O derivado proposto utilizou o geniposídeo como molécula-base, um metabólito secundário que já possui afinidade pelo receptor. De acordo com as análises realizadas, a molécula analisada pode ser considerada promissora nas pesquisas de novos fármacos para COVID-19, uma vez se ligou a dois aminoácidos da tríade catalítica responsáveis pela inibição da protease, assim como demais aminoácidos importantes, apresentando menor, e consequentemente melhor valor de afinidade de ligação comparados com a molécula-base e os fármacos sintéticos já disponíveis no mercado.

References

ALMEIDA JO, OLIVEIRA VRT, AVELAR JLS, MOITA BS, LIMA LM. COVID-19: Fisiopatologia e Alvos para Intervenção Terapêutica. Rev. Virtual Quim., 2020, 12 (6), 1464-1497.

Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nature Medicine. 2020;26(4):450-2.

Barreiro EJ, Fraga CAM. Qúimica Medicinal: As bases Moleculares da Ação dos Fármacos, 3ª ed, Artmed, Porto Alegre, 2015.

Brandão MCR. Novos nitratos orgânicos derivados de biomassas como potenciais fármacos cardiovasculares. Centro de Ciências Exatas e da Natureza (CCEN), Universidade Federal da Paraíba, João Pessoa-PB, 2017.

Bugge TH, Antalis TM, Wu Q. Type II transmembrane serine proteases. J Biol Chem . 2009 Aug 28;284(35):23177-81. doi: 10.1074/jbc.R109.021006.

Centers for Disease Control and Prevention (CDC). The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(2):145- 51. China, 202. China CDC Weekly.2020,2(8):113-122.

Dai L, Gao GF. Viral targets for vaccines against COVID-19. Nature Reviews Immunology 2020; 21: 73–82.

Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020 Feb 19. [Epub ahead of print].

Fraser BJ, Beldar S, Hutchinson A, Li Y, Seitova A, Manar D, Kwon D, Tan R, Wilson RP, Leopold K, Subramaniam S, Halabelian L, Arrowsmith, C.H., Bérnard F. Structure, activity and inhibition of human TMPRSS2, a protease implicated in SARS-CoV-2 activation. bioRxiv preprint, 2021. doi: https://doi.org/10.1101/2021.06.23.449282

Hassan Y, Osman AK, Altyeb A. Noninvasive management of hemangioma and vascular malformation using intralesional bleomycin injection. 2013 Jan;70(1):70-3. doi: 10.1097/SAP.0b013e31824e298d.

Huang B, Chen P, Huang L, Li S, Zhu R, Sheng T, Yu W, Chen Z, Wang T. Geniposide attenuates post-ischaemic neurovascular damage via GluN2A/AKT/ERK-dependent mechanism. Cell Physiol Biochem, 2017;43:705–716. https://doi.org/10.1159/000480657.

Huang H, Zhang X, Huang Z, Zhang Y, Zhou Z. Geniposide reverses multidrug resistance in vitro and in vivo by inhibiting the efflux function and expression of P-glycoprotein, 2020 May; 25(10): 2271. doi: 10.3892/etm.2016.4011.

Hoffman M, Weber HK, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052

NCBI Data in XML. Disponível em: <https://www.ncbi.nlm.nih.gov/>., acesso em Jul, 2021.

SWISS-ADME. Disponível em: <https://swissmodel.expasy.org/interactive>., acesso em Jul, 2021. PDB – PROTEIN DATA BANK. Disponível em: <https://www.rcsb.org/structure/7MEQ>., acesso em Jul, 2021.

Jankun, J. COVID-19 pandemic; transmembrane protease serine 2 (TMPRSS2) inhibitors as potential therapeutics for SARS-CoV-2 coronavirus. Translation: The University of Toledo Journal of Medical Sciences, 7:1-5, 2020. doi: 10.46570/utjms.vol7-2020-361.

Kawase M, Shirato K, Hoek LVD, Taguchi F, Matsuyama S. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. 2012 Jun;86(12):6537-45. doi: 10.1128/JVI.00094-12.

Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. Califórnia, Estados Unidos, 2009.

Nishizawa M, Izuhara R, Kaneko K, Koshihara Y, Fujimoto Y. 5-Lipoxygenase inhibitors isolated from Gardeniae fructus, 1988 Jan;36(1):87-95. doi: 10.1248/cpb.36.87.

Rahman N, Basharat Z, Yousuf M, Castaldo G, Rastrelli L, Khan H. Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2), 2020, 25(10), 2271; https://doi.org/10.3390/molecules25102271.

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine, March, 2020. https://doi.org/10.1007/s00134-020-05991-x.

Roomi MS, Khan YD. Potential Compounds for the Inhibition of TMPRSS2. ChemRxiv. Preprint. 2020. https://doi.org/10.26434/chemrxiv.12727787.v1.

Santos MIS, Kaplan MAC. Biosynthesis significance of iridoids in chemosystematics. J. Braz. Chem. Soc. 12(2), 2001. Doi:10.1590/S0103-50532001000200004.

Sonawane KD, Barale SS, Dhanavade MJ, Waghmare SR, Nadaf NH, Kamble SA, Mohammed AA, Makandar AM, Fandilolu PM, Dound AS, Naik NM, More, V. B. Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modeling approach. Informatics in Medicine Unlocked, 24, 100597. 2021. doi:10.1016/j.imu.2021.100597

Shan M, Yu S, Yan H, Guo S, Xiao W, Wang Z, Zhang L, Ding A, Wu Q, Li SFY. A review on the phytochemistry, pharmacology, pharmacokinetics and toxicology of geniposide, a natural product. Molecules, 2017, 22(10). doi: 10.3390/molecules22101689.

Strabelli TMV, Uip DE. COVID-19 e o Coração. SBC Editorial, São Paulo, Brasil.2020 DOI: https://doi.org/10.36660/abc.20200209.

Strope JD, Chau CH, Figg WD. TMPRSS2: Potential Biomarker for COVID-19 Outcomes. 2020 Jul;60(7):801-807. doi: 10.1002/jcph.1641.

Tegally H, et al. Emergence and Rapid Spread of a New Severe Acute Respiratory Syndrome-related Coronavirus 2 (Sars-cov-2) Lineage with Multiple Spike Mutations in South Africa. Preprint from medRxiv.

Volz E, Hill V, McCrone JT, et al. Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity. Cell 2021; 184: 64-75.e11.

Yamamoto M, Matsuyama S, Li X, Takeda M, Kawaguchi Y, Inoue JI, Matsuda Z. Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay. 2016 Oct 21;60(11):6532-6539. doi: 10.1128/AAC.01043-16.

Zhang C, Wang N, Tan HY, Guo W, Chen F, Zhong Z, Man K, Tsao SW, Lao L, Feng Y. Direct inhibition of TLR4/MyD88 pathway by geniposde suppresses HIF1α-independent VEGF expression and angiogenesis in hepatocellular carcinoma, British Journal of PharmacologyVolume 177, Issue 14 p. 3240-3257, 2020. doi: 10.1111/bph.15046.

Zhang T, Wu Q, Zhang Z. Probable pangolin origin of SARS-CoV-2 associatedwith the COVID-19 outbreak. Curr Biol. 2020;30(8):1578. doi: 10.1016/j.cub.2020.03.063.

Published

2022-06-08

How to Cite

Ximenes, J. de A., Rocha, A. M., Bezerra, N. F., Branco, C. H. L. G. T., da Silva, R. V. A., & Guilhon-Simplicio, F. (2022). Modelagem molecular de derivado do geniposídeo como inibidor da TMPRSS2 contra a COVID-19 / Molecular modeling of geniposide derivative as TMPRSS2 inhibitor Against COVID-19. Brazilian Journal of Development, 8(6), 45109–45122. https://doi.org/10.34117/bjdv8n6-167

Issue

Section

Original Papers