Analisis in silico interaksi senyawa kurkuminoid terhadap enzim main protease 6LU7 dari SARS-CoV-2

Winih Kinasih et al., Duta Pharma Journal, doi:10.47701/djp.v3i1.2904, Jun 2023

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Curcumin for COVID-19

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In Silico study of the interaction between curcumin and its derivatives with the main protease enzyme from SARS-CoV-2. The compounds tested were curcumin, bisdemethoxycurcumin, and demethoxycurcumin. All compounds met the requirements of Lipinski's Rule of Five, indicating they have drug-like properties. Bisdemethoxycurcumin had the highest binding affinity (lowest docking score of -6.7 kcal/mol) to the protease, suggesting it is the most potent inhibitor of the enzyme. Bisdemethoxycurcumin shared the most amino acid residues with the reference ligand favipiravir. This suggests bisdemethoxycurcumin has potential as an antiviral agent against SARS-CoV-2 by inhibiting its main protease enzyme.

55 preclinical studies support the efficacy of curcumin for COVID-19:

28 In Silico studies1-28

26 In Vitro studies1,3,5,9,11,15,21,25,29-46

1 In Vivo animal study9

In Silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,3,4,9,14,16,22,25 (and specifically the receptor binding domainB,2,12,15,18), M^proC,2-4,9,11,13-15,17,18,20,23,25,26,28,43, RNA-dependent RNA polymeraseD,2-4,15,24, PLproE,4, ACE2F,16,17,19, nucleocapsidG,10,27, nsp10H,27, and helicaseI,32 proteins, and inhibition of spike-ACE2 interactionJ,1. In Vitro studies demonstrate inhibition of the spikeA,37 (and specifically the receptor binding domainB,46), M^proC,21,37,43,45, ACE2F,46, and TMPRSS2K,46 proteins, and inhibition of spike-ACE2 interactionJ,1,30. In Vitro studies demonstrate efficacy in Calu-3L,44, A549M,37, 293TN,5, HEK293-hACE2O,21,35, 293T/hACE2/TMPRSS2P,36, Vero E6Q,11,15,25,35,37,39,40,42,44, and SH-SY5YR,34 cells. Curcumin is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants12, decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells42, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress5, may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts31, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity38.

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a. The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.

b. The receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.

c. The main protease or M^pro, also known as 3CL^pro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting M^pro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.

d. RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.

e. The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.

f. The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.

g. The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.

h. Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.

i. The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.

j. The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.

k. Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.

l. Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.

m. A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.

n. 293T is a human embryonic kidney cell line that can be engineered for high ACE2 expression and SARS-CoV-2 susceptibility. 293T cells are easily transfected and support high protein expression.

o. HEK293-hACE2 is a human embryonic kidney cell line with high ACE2 expression and SARS-CoV-2 susceptibility. Cells have been transfected with a plasmid to express the human ACE2 (hACE2) protein.

p. 293T/hACE2/TMPRSS2 is a human embryonic kidney cell line engineered for high ACE2 and TMPRSS2 expression, which mimics key aspects of human infection. 293T/hACE2/TMPRSS2 cells are very susceptible to SARS-CoV-2 infection.

q. Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.

r. SH-SY5Y is a human neuroblastoma cell line that exhibits neuronal phenotypes. It is commonly used as an in vitro model for studying neurotoxicity, neurodegenerative diseases, and neuronal differentiation.

Winih Kinasih et al., 30 Jun 2023, peer-reviewed, 3 authors. Contact: ahone.far02@gmail.com.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

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ANALISIS IN SILICO INTERAKSI SENYAWA KURKUMINOID TERHADAP ENZIM MAIN PROTEASE 6LU7 DARI SARS-COV-2

Angkininta Ayu, Winih Kinasih, Fadilah Qonitah

Covid-19 merupakan penyakit yang disebabkan coronavirus jenis baru (SARS-CoV-2) di akhir tahun 2019. Sampai saat ini tidak ada obat khusus yang tersedia untuk mengobati penyakit ini. Pengobatan tradisional telah memainkan peran positif dalam memerangi Covid-19. Beberapa senyawa aktif mulai dilakukan penelitian untuk menangkal virus Covid-19 salah satunya adalah senyawa kurkumin. Kurkumin merupakan senyawa aktif dari tanaman kunyit dan temulawak. Berdasarkan penelitian dilaporkan kurkumin dapat menghambat agregasi trombosit, antidiabetes, antitumor, efek antiinflamasi, efek antioksidan, dan antivirus. Penelitian ini bertujuan untuk mengetahui interaksi antara senyawa kurkuminoid terhadap enzim main protease 6LU7 dari SARS CoV-2 serta senyawa kurkuminoid yang dapat berikatan dengan enzim main protease 6LU7 dari SARS CoV-2. Penelitian ini termasuk jenis penelitian eksperimental secara in silico. Hasil penelitian ini diperoleh senyawa uji kurkumin dan turunannya yaitu kurkumin, bisdemetoksikurkumin, dan demetoksikurkumin telah memenuhi syarat hukum Lipinksi Rule of Five. Bisdemetoksikurkumin memiliki kemampuan sebagai antivirus SARS-CoV-2 karena memiliki persamaan residu asam amino paling banyak dengan ligan pembanding (Favipiravir) yaitu residu ASN A

DAFTAR PUSTAKA

DOI record: { "DOI": "10.47701/djp.v3i1.2904", "ISSN": [ "2829-811X", "2830-7054" ], "URL": "http://dx.doi.org/10.47701/djp.v3i1.2904", "abstract": "Covid-19 merupakan penyakit yang disebabkan coronavirus jenis baru (SARS-CoV-2) di akhir tahun 2019. Sampai saat ini tidak ada obat khusus yang tersedia untuk mengobati penyakit ini. Pengobatan tradisional telah memainkan peran positif dalam memerangi Covid-19. Beberapa senyawa aktif mulai dilakukan penelitian untuk menangkal virus Covid-19 salah satunya adalah senyawa kurkumin. Kurkumin merupakan senyawa aktif dari tanaman kunyit dan temulawak. Berdasarkan penelitian dilaporkan kurkumin dapat menghambat agregasi trombosit, antidiabetes, antitumor, efek antiinflamasi, efek antioksidan, dan antivirus. Penelitian ini bertujuan untuk mengetahui interaksi antara senyawa kurkuminoid terhadap enzim main protease 6LU7 dari SARS CoV-2 serta senyawa kurkuminoid yang dapat berikatan dengan enzim main protease 6LU7 dari SARS CoV-2. Penelitian ini termasuk jenis penelitian eksperimental secara in silico. Hasil penelitian ini diperoleh senyawa uji kurkumin dan turunannya yaitu kurkumin, bisdemetoksikurkumin, dan demetoksikurkumin telah memenuhi syarat hukum Lipinksi Rule of Five. Bisdemetoksikurkumin memiliki kemampuan sebagai antivirus SARS-CoV-2 karena memiliki persamaan residu asam amino paling banyak dengan ligan pembanding (Favipiravir) yaitu residu ASN A:142; GLY A:143; CYS A:145; HIS A:163; HIS A:172; LEU A:141; SER A:144; GLU A:166; PHE A:140 dengan docking score sebesar -6,7 kkal/mol.", "author": [ { "affiliation": [], "family": "Abdul", "given": "Ahwan", "sequence": "first" }, { "affiliation": [], "family": "Winih Kinasih", "given": "Angkininta Ayu", "sequence": "additional" }, { "affiliation": [], "family": "Qonitah", "given": "Fadilah", "sequence": "additional" } ], "container-title": "Duta Pharma Journal", "container-title-short": "DJP", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2023, 7, 31 ] ], "date-time": "2023-07-31T05:14:10Z", "timestamp": 1690780450000 }, "deposited": { "date-parts": [ [ 2023, 7, 31 ] ], "date-time": "2023-07-31T05:14:11Z", "timestamp": 1690780451000 }, "indexed": { "date-parts": [ [ 2023, 8, 1 ] ], "date-time": "2023-08-01T04:25:10Z", "timestamp": 1690863910582 }, "is-referenced-by-count": 0, "issue": "1", "issued": { "date-parts": [ [ 2023, 6, 30 ] ] }, "journal-issue": { "issue": "1", "published-online": { "date-parts": [ [ 2023, 6, 30 ] ] } }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "unspecified", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 6, 30 ] ], "date-time": "2023-06-30T00:00:00Z", "timestamp": 1688083200000 } } ], "link": [ { "URL": "https://ojs.udb.ac.id/index.php/DJP/article/download/2904/2115", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://ojs.udb.ac.id/index.php/DJP/article/download/2904/2115", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "27561", "original-title": [], "prefix": "10.47701", "published": { "date-parts": [ [ 2023, 6, 30 ] ] }, "published-online": { "date-parts": [ [ 2023, 6, 30 ] ] }, "publisher": "Universitas Duta Bangsa Surakarta", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://ojs.udb.ac.id/index.php/DJP/article/view/2904" } }, "score": 1, "short-title": [], "source": "Crossref", "subtitle": [], "title": "ANALISIS IN SILICO INTERAKSI SENYAWA KURKUMINOID TERHADAP ENZIM MAIN PROTEASE 6LU7 DARI SARS-COV-2", "type": "journal-article", "volume": "3" }

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