Hidayah, Rizka Nurul and dr.Dewi Santosaningsih,, SpMK,M.Kes,PhD and Prof.Dr.Roihatul Mutiah,, SF.,M.Kes.,Apt. (2022) Aktivitas senyawa Curcumin, Demethoxycurcumin, Bisdemethoxycurcumin dan Cyclocurcumin dalam Curcuma longa terhadap Nucleocapsid, Non-Structural Protein 3 dan 5 pada SARS-CoV-2. Magister thesis, Universitas Brawijaya.
Abstract
SARS-CoV-2 memiliki angka reproduksi (R0) yang lebih tinggi daripada SARS-CoV-1, yang menunjukkan penyebaran yang jauh lebih cepat. dibandingkan SARS-CoV dan pandemi influenza 1918. Pada kasus berat perburukan secara cepat dan progresif dalam beberapa hari menimbulkan kondisi kritis bahkan meninggal dunia. Mengingat tingkat keparahan infeksi dan belum adanya pengobatan mutlak yang teruji klinis, terapi yang menargetkan replikasi virus dapat menjadi pilihan yang solutif. Genom SARS-CoV-2 mengkode dua poliprotein besar, pp1a dan pp1ab. Poliprotein ini dibelah dan diubah dalam non-structural protein (NSP) matur oleh dua protease yaitu non-structural protein 5 (NSP5) dan non-structural protein (NSP3) yang dikodekan oleh ORF 1a /b. Selama proses replikasi, genom RNA virus diikat nucleocapsid dan dikemas menjadi kompleks ribonukleoprotein (RNP) yang penting untuk mempertahankan konformasi RNA untuk replikasi dan salin genom. Mempertimbangkan aktivitas penting dalam replikasi virus, penghambatan terhadap aktivitas protein NSP3, NSP5 dan nucleocapsid merupakan target potensial untuk aktivitas antivirus. Senyawa yang dapat menghambat proses replikasi virus ini berpeluang untuk dikembangkan sebagai antivirus. Curcuma longa atau kunyit telah didokumentasikan memiliki spektrum efek farmakologis yang luas. Curcuma longa memiliki sejumlah kandungan senyawa aktif curcumin (Curcumin I), demethoxycurcumin (curcumin II), bisdemethoxycurcumin (curcumin III), and cyclocurcumin (curcumin IV). Berbeda dengan Curcumin, senyawa aktif lainnya ini kurang mendapatkan perhatian peneliti. Curcumin dan analognya seperti demethoxycurcumin, bisdemethoxycurcumin, cyclocurcumin yang mengandung farmakofor 1,5-diaryl-3-oxo-1,4-pentadienil, diperkirakan berinteraksi di tempat pengikatan primer dan bio-tiol dari neoplasma yang rentan. Farmakofor kelompok metoksifenol sejajar di situs tambahan dan juga memengaruhi aktivitas biologisnya. Efek farmakologi Curcumin disebabkan adanya gugus hidroksil fenolik dan karbonil Curcumin yang membentuk ikatan hidrogen molekul target yang dapat berupa enzim maupun faktor transkripsi. Ikatan ini mengganggu sistem biologi organisme seperti steroidogenesis dan ekspresi. Tujuan penelitian memahami efek farmakologis dan keamanan Curcuma longa sebagai potensi terapi erhadap SAR-CoV2 melalui Studi in silico dengan teknik molekular docking. Senyawa terlebih dahulu di skrinning menggunakan swisADME dengan kriteria hukum lima Lipinski. Senyawa yang lolos skrinning didocking dengan NSP3, NSP5 dan Nucleocapsid menggunakan Molegro molecular docking dengan mengevaluasi aktivitas senyawa melalui Rerank Score, H-bond dan RMSD. Keamanan senyawa juga diuji melalui uji toksisitas menggunakan pkCSM & Protox Online Tool untukmengetahui LD50, Ames toxicity dan Hepatotoxycity. Studi menunjukkan afinitas pengikatan senyawa dalam Curcuma longa terhadap reseptor pada virus SARS-CoV2. Basis data PubChem digunakan untuk mendapatkan profil metabolisme Curcuma longa. Interaksi senyawa dengan nukleokapsid dianalisis menggunakan molecular docking dengan Molegro Virtual Docker. Analisis bioinformatika berdasarkan rerank score. Hasil uji menunjukkan potensi senyawa menghambat replikasi virus, fisikomia, farmakokinetik dan keamanan dari toksisitas Curcuma Longan dalam rentang aman untuk dikonsumsi dan sebagai terapi. Analisis hasil penelitian mengunakan uji Molegro Viewer menunjukkan bahwa ikatan senyawa Curcuma Longa lebih stabil dari pada ikatan native ligand berdasarkan nilai rerank score yang lebih rendah dan kesamaan residu asam amino yang dimiliki. Dapat disimpulkan bahwa Studi ini mengungkapkan bahwa C. longa berpotensi untuk dikembangkan sebagai agen antivirus melalui penghambatan replikasi pada SARS-CoV-2 dengan target replikasinya dimediasi oleh NSP3, NSP5 dan Nucleocapsid.
English Abstract
SARS-CoV-2 has a higher reproduction number (R0) than SARS-CoV-1, indicating a much faster spread. compared to SARS-CoV and the 1918 influenza pandemic. In severe cases, rapid and progressive deterioration within a few days can lead to critical conditions and even death. Given the severity of the infection and the absolute absence of a clinically tested treatment, therapy that targets viral replication can be a solutive option. The SARS-CoV-2 genome encodes two large polyproteins, pp1a and pp1ab. This polyprotein is cleaved and converted into mature non-structural protein (NSP) by two proteases namely non-structural protein 5 (NSP5) and non-structural protein (NSP3) encoded by ORF 1a /b. During the replication process, the viral RNA genome is nucleocapsid bound and packaged into a ribonucleoprotein complex (RNP) which is important for maintaining the conformation of the RNA for genome replication and copying. Considering their important activity in viral replication, inhibition of NSP3, NSP5 and nucleocapsid protein activity is a potential target for antiviral activity. Compounds that can inhibit the process of viral replication have the opportunity to be developed as antivirals. Curcuma longa or turmeric has been documented to have a wide spectrum of pharmacological effects. Curcuma longa contains a number of active compounds curcumin (Curcumin I), demethoxycurcumin (curcumin II), bisdemethoxycurcumin (curcumin III), and cyclocurcumin (curcumin IV). In contrast to curcumin, these other active compounds have received less attention from researchers. Curcumin and its analogues such as demethoxycurcumin, bisdemethoxycurcumin, cyclocurcumin containing the pharmacophore 1,5-diaryl-3-oxo-1,4-pentadienyl, are thought to interact at the primary binding sites and bio-thiols of susceptible neoplasms. The pharmacophore of the methoxyphenol groups aligns at additional sites and also influences their biological activity. The pharmacological effects of curcumin are due to the presence of phenolic hydroxyl groups and curcumin carbonyl groups which form hydrogen bonds to target molecules which can be enzymes or transcription factors. This bond disrupts the organism's biological systems such as steroidogenesis and expression. The aim of this research is to understand the pharmacological and safety effects of Curcuma longa as a potential therapy for SAR-CoV2 through in silico studies using molecular docking techniques. Compounds were first screened using swisADME with Lipinski's five law criteria. Compounds that passed the screening were docked with NSP3, NSP5 and Nucleocapsid using Molegro molecular docking by evaluating the activity of the compounds through Rerank Score, H-bond and RMSD. The safety of the compounds was also tested through toxicity tests using the pkCSM & Protox Online Tool to determine LD50, Ames toxicity and Hepatotoxycity. Studies show the binding affinity of compounds in Curcuma longa for receptors on the SARS-CoV2 virus. The PubChem database was used to obtain the metabolic profile of Curcuma longa. The interactions of the compounds with nucleocapsids were analyzed using molecular docking with Molegro Virtual Docker. Bioinformatics analysis based on rerank score. The test results showed the potential of the compound to inhibit viral replication, physicochemistry, pharmacokinetics and safety of the toxicity of Curcuma Longan within the safe range for consumption and as therapy. Analysis of the research results using the Molegro Viewer test showed that the Curcuma Longa bond was more stable than the native ligand bond based on the lower rerank score and the similarity of the amino acid residues it had. It can be concluded that this study reveals that C. longa has the potential to be developed as an antiviral agent by inhibiting replication in SARS-CoV-2 with its replication targets mediated by NSP3, NSP5 and Nucleocapsid.
Other obstract
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| Item Type: | Thesis (Magister) |
|---|---|
| Identification Number: | 0422060180 |
| 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: | 09 May 2023 06:18 |
| Last Modified: | 09 May 2023 06:18 |
| URI: | http://repository.ub.ac.id/id/eprint/199094 |
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