Nafisa, Belia Bima and Prof.Dr.dr. Sanarto Santoso, DTM&H.,SpMK.(K) and Dr. Zainabur Rahmah, M.Si (2023) Aktivitas Senyawa Eleutherine, Isoeleutherine, Eleuthinone dan Elecanacine dalam Eleutherine palmifolia (L.) Merr terhadap Nonstructural Protein 3 dan 5 pada SARS-COV-2 Secara In Silico. Magister thesis, Universitas Brawijaya.
Abstract
Corona virus disease 2019 (COVID-19) sudah mewabah ke segala dunia yang berbahaya bagi morbiditas serta mortilitas. Ini adalah wabah menular karena terinfeksi SARS-CoV-2 (Severe acute respiratory syndrome corona virus 2). Virus tersebut terdapat protein, satu diantaranya ialah NSP (nonstructural protein) dengan pengkodean 2 poliprotein besar, pp1a serta pp1ab. Kedua poliprotein tersebut dibelah oleh dua protease, diantaranya yaitu nonstructural protein 3 (NSP3) dan nonstructural protein 5 (NSP5) yang merupakan komponen penting dalam replikasi virus yang membantu pelepasan protein esensial virus atau multiplikasi virus. Mempertimbangkan replikasi virus penting untuk aktivitas antivirus, sehingga senyawa yang dapat menghambat proses replikasi ini berpeluang untuk dikembangkan sebagai antivirus. Hal ini membentuk peneliti meningkatkan penggunaan senyawa dari bahan herbal sebagai alternatif yang memiliki efek terhadap SARS-CoV-2, salah satunya Eleutherine palmifolia (L.) Merr. Penelitian ini bertujuan untuk memprediksi aktivitas antiviral, sifat fisikokimia dan toksisitas dari senyawa metabolit sekunder Eleutherine palmifolia (L.) Merr yang meliputi senyawa eleutherine, isoeleutherine, eleuthinone dan elecanacine. Prediksi aktivitas antiviral ditinjau berdasarkan interaksi ligan dengan reseptor NSP3 dan NSP5 menggunakan Molegro Virtual Docker (MVD) 6.0. Prediksi sifat fisikokimia mengacu pada Lipinski's rule of five (Lipinski RO5) dan topological polar surface area (TPSA) menggunakan swissADME. Prediksi toksisitas berdasarkan klasifikasi LD50 dan parameter ames toxicity, hepatotoxicity dan skin sensitization menggunakan ProTox-II dan pkCSM. Berdasarkan analisis bioinformatika, semua senyawa uji diduga memiliki potensi aktivitas antivirus melalui penghambatan terhadap reseptor NSP3 (7JIT) yang ditinjau dari rerank score dengan afinitas yang lebih tinggi dibandingkan dengan obat pembanding Ribavirin. Rerank score (Kkal/mol) dari eleutherine yaitu -102.853, isoeleutherine -108.493, eleuthinone -108.005 dan elecanacine -104.640. Rerank score semua senyawa lebih rendah dari obat Ribavirin (-94.195). Sedangkan pada reseptor NSP5 (7K40), hanya elecanacine yang diduga memiliki potensi aktivitas antivirus yang ditunjukkan melalui interaksi dengan reseptor dengan afinitas yang mendekati nilai energi ikatan dari obat pembanding Remdesivir. Rerank score (Kkal/mol) dari elecanacine yaitu -123.718 dan Remdesivir yaitu -123.955. Berdasarkan analisis asam amino, pada reseptor NSP3 semua senyawa terdapat residu asam amino yang berperan penting untuk menginduksi penghambatan reseptor NSP3, yang terdiri dari Asp164, Glu167, Tyr264, Tyr268 dan Gln269. Sedangkan pada reseptor NSP5, semua senyawa kecuali eleuthinone terdapat residu asam amino yang berperan penting untuk menginduksi penghambatan reseptor NSP5 yaitu Glu166 dan Cys145. Semua senyawa dalam penelitian ini memenuhi Lipinski RO5 serta TPSA yang baik, kecuali Remdesivir. Semua senyawa memiliki nilai LD50 pada kelas toksisitas IV, kecuali Remdesivir pada kelas toksisitas V. Semua senyawa diprediksi aman, kecuali elecanacine diprediksi bersifat mutagenik dan eleuthinone diprediksi bersifat hepatotoksik. Dapat disimpulkan bahwa senyawa eleutherine, isoeleutherine, eleuthinone dan elecanacine diduga memiliki potensi aktivitas antivirus melalui penghambatan terhadap reseptor NSP3 SARS-CoV-2 dan senyawa elecanacine diduga memiliki potensi aktivitas antivirus melalui penghambatan terhadap reseptor NSP5 SARS-CoV-2. Namun, temuan ini masih memerlukan validasi lanjut secara in vitro serta in vivo.
English Abstract
Corona virus disease 2019 (COVID-19) has spread throughout the world which is dangerous for morbidity and mortality. This is a contagious epidemic due to infection with SARS-CoV-2 (Severe acute respiratory syndrome corona virus 2). The virus contains proteins, one of which is NSP (nonstructural protein) encoding 2 large polyproteins, pp1a and pp1ab. The two polyproteins are cleaved by two proteases, including nonstructural protein 3 (NSP3) and nonstructural protein 5 (NSP5) which are important components in viral replication that help release essential viral proteins or virus multiplication. Considering that virus replication is important for antiviral activity, so compounds that can inhibit this replication process have the opportunity to be developed as antivirals. This has made researchers increase the use of compounds from herbal ingredients as alternatives that have an effect on SARS-CoV-2, one of which is Eleutherine palmifolia (L.) Merr. This study aims to predict the antiviral activity, physicochemical properties and toxicity of secondary metabolites Eleutherine palmifolia (L.) Merr consisting of eleutherine, isoeleutherine, eleuthinone and elecanacine compounds. Predictions of antiviral activity were reviewed based on ligand interactions with NSP3 and NSP5 receptors using Molegro Virtual Docker (MVD) 6.0. The prediction of physicochemical properties refers to Lipinski's rule of five (Lipinski RO5) and topological polar surface area (TPSA) using swissADME. Toxicity prediction based on LD50 classification and ames toxicity, hepatotoxicity and skin sensitization parameters using ProTox-II and pkCSM. Based on bioinformatics analysis, all tested compounds were suspected to have potential antiviral activity through inhibition of the NSP3 receptor (7JIT) in terms of rerank scores with higher affinity compared to the comparator drug Ribavirin. Rerank scores (Kcal/mol) for eleutherine is -102.853, isoeleutherine -108.493, eleuthinone -108.005 and elecanacine -104.640. Rerank score of all compounds is lower than Ribavirin (-94.195). Whereas in the NSP5 receptor (7K40), only elecanacine is thought to have potential antiviral activity as shown by interaction with the receptor with an affinity close to the binding energy value of the comparator drug Remdesivir. The rerank score (Kcal/mol) for elecanacine is -123,718 and Remdesivir is -123,955. Based on amino acid analysis, the NSP3 receptors in all compounds contain amino acid residues which play an important role in inducing inhibition of NSP3 receptors, which consist of Asp164, Glu167, Tyr264, Tyr268 and Gln269. Whereas in the NSP5 receptor, all compounds except eleuthinone contain amino acid residues that play an important role in inducing inhibition of the NSP5 receptor, namely Glu166 and Cys145. All compounds in this study met good Lipinski RO5 and TPSA, except for Remdesivir. All compounds have an LD50 value in toxicity class IV, except for Remdesivir in toxicity class V. All compounds are predicted to be safe, except for elecanacine which is predicted to be mutagenic and eleuthinone which is predicted to be hepatotoxic. Can be concluded that the compounds eleutherine, isoeleutherine, eleuthinone and elecanacine are thought to have potential antiviral activity through inhibition of the SARS-CoV-2 NSP3 receptor and the compound elecanacine is thought to have potential antiviral activity through inhibition of the SARS-CoV-2 NSP5 receptor. However, these findings still require further validation in vitro and in vivo.
| Item Type: | Thesis (Magister) |
|---|---|
| Identification Number: | 0423060026 |
| Subjects: | 600 Technology (Applied sciences) > 616 Diseases > 616.02 Special topics of disease > 616.025 Medical emergencies / Emergency medicine / Emergency nursing / Triage (Medicine) |
| Divisions: | S2/S3 > Magister Ilmu Biomedis, Fakultas Kedokteran |
| Depositing User: | Endang Susworini |
| Date Deposited: | 06 Nov 2023 05:14 |
| Last Modified: | 06 Nov 2023 05:14 |
| URI: | http://repository.ub.ac.id/id/eprint/204378 |
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