Indonesian Journal of Medical Chemistry and Bioinformatics


The SARS-Coronavirus 2 (SARS-CoV-2) outbreak is a serious global public health threat. Researchers around the world are conducting mass research to control this epidemic, starting from the discovery of vaccines, to new drugs that have specific activities as antivirals. Drug repurposing is a potential method of using drugs with known activity for reuse as COVID-19 therapy. This method has the advantage that it can reduce costs and also the duration in the development of potential drugs. The initial step in drug repurposing can be done computationally to determine the effectiveness and specificity of the drug on the target protein. Molecular docking analysis can see the specific interactions of potential compounds with target proteins by analyzing the energy of the bonds formed. The spike protein of SARS-CoV-2 is a major target in the design and discovery of new drugs for the treatment of Covid-19 disease. In addition, transmembrane protein serine protease (TMPRSS2) from host cells has been shown to have an important role in the proteolytic cleavage of viral spike protein to the ACE2 receptor present in human cells. Based on screening studies, it is known that there are several drugs that have been established that have the potential to inhibit the SARS-CoV-2 transfection mechanism into host cells. 10 potential drug candidates used in this study namely Arbecacin, Bromhexine hydrochloride, Hydroxychloroquine, Camostat mesylate, Darunavir, Dequalinium, Fleroxacin, Lopinavir, Remdesivir, and Octopamine were used in molecular docking. Docking analysis revealed that there were three potential compounds, namely Bromhexine hydrochloride, Camostat mesylate and Octopamine with low binding affinity and inhibition constants. Based on the docking result, Camostat mesylate as the best candidate has a high specific binding affinity for the Ser441 and Asp435 residues present in the TMPRSS2 catalytic triad. Thus, these results reveal the mechanism of inhibition of TMPRSS2 by the known inhibitor Camostat mesylate in detail at the molecular level. Where, Camostat mesylate has a strong bond. This structural information could also be useful for designing and discovering new inhibitors of TMPRSS2, which may be useful for preventing the entry of SARS-CoV 2 into human cells.

Bahasa Abstract

Wabah SARS-Coronavirus 2 (SARS-CoV-2) adalah ancaman kesehatan masyarakat global yang serius. Para peneliti di seluruh dunia sedang melakukan penelitian massal untuk mengendalikan epidemi ini, mulai dari penemuan vaksin, hingga obat baru yang memiliki aktivitas spesifik sebagai antivirus. Penggunaan kembali obat adalah metode potensial untuk menggunakan obat-obatan dengan aktivitas yang diketahui dapat digunakan kembali sebagai terapi COVID-19. Metode ini memiliki kelebihan yaitu dapat menekan biaya dan juga durasi dalam pengembangan obat potensial. Langkah awal dalam repurposing obat dapat dilakukan secara komputasi untuk menentukan efektivitas dan spesifisitas obat pada protein target. Analisis molekuler docking dapat melihat interaksi spesifik senyawa potensial dengan protein target dengan menganalisis energi ikatan yang terbentuk. Protein lonjakan SARS-CoV-2 adalah target utama dalam desain dan penemuan obat baru untuk pengobatan penyakit Covid-19. Selain itu, protein serin protease transmembran (TMPRSS2) dari sel inang telah terbukti memiliki peran penting dalam pembelahan proteolitik protein lonjakan virus ke reseptor ACE2 yang ada dalam sel manusia. Berdasarkan studi penapisan, diketahui ada beberapa obat yang telah ditetapkan berpotensi menghambat mekanisme transfeksi SARS-CoV-2 ke dalam sel inang. 10 kandidat obat potensial yang digunakan dalam penelitian ini yaitu Arbecacin, Bromhexine hydrochloride, Hydroxychloroquine, Camostat mesylate, Darunavir, Dequalinium, Fleroxacin, Lopinavir, Remdesivir, dan Octopamine digunakan dalam molecular docking. Analisis docking mengungkapkan bahwa ada tiga senyawa potensial, yaitu Bromhexine hidroklorida, Camostat mesylate dan Octopamine dengan afinitas pengikatan dan konstanta penghambatan yang rendah. Camostat mesylate sebagai kandidat terbaik memiliki ikatan spesifik dengan afinitas tinggi untuk residu Ser441 dan Asp435 yang ada dalam triad katalitik TMPRSS2. Dengan demikian, hasil ini mengungkapkan mekanisme penghambatan TMPRSS2 oleh inhibitor Camostat mesylate yang diketahui secara rinci pada tingkat molekuler. Dimana, Camostat mesylate memiliki ikatan yang kuat. Informasi struktural ini juga dapat berguna untuk merancang dan menemukan inhibitor baru TMPRSS2, yang mungkin berguna untuk mencegah masuknya SARS-CoV-2 ke dalam sel manusia.


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