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Abstract
The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than −8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.
Highlights
The coronavirus SARS-CoV-2, responsible for the pandemic which started in Wuhan, China, during the latter part of 2019, has spread to 213 countries, areas and territories according to the WHO [1,2] by April 16th 2020 and continues to spread, infecting approximately 84,500 and causing the death of approximately 8000 people daily
Since the 3D structure of the active site of the enzyme is crucial for catalytic activity, we proceeded to a comparison of the SARS-CoV-2 main protease, main protease structure (Mpro), with the HIV-1 protease, the HCV protease (NS3 protein) and the human proteases Dipeptidyl Peptidase-4 (DPP-4), thrombin, Factor Xa, renin and angiotensin-converting enzyme (ACE), which constitute known drug targets with approved inhibitors
Significant 3D similarity was found between the SARS-CoV-2 and the HCV protease (p = 1.34 × 10−4 ) as well as between the SARS-CoV-2 protease and α-thrombin (p = 7.42 × 10−4 )
Summary
The coronavirus SARS-CoV-2, responsible for the pandemic which started in Wuhan, China, during the latter part of 2019, has spread to 213 countries, areas and territories according to the WHO [1,2] by April 16th 2020 and continues to spread, infecting approximately 84,500 and causing the death of approximately 8000 people daily. Among the drugs approved or developed for other purposes that have been proposed for the treatment of SARS-CoV-2 and are under clinical trials, most are enzyme inhibitors, targeting the RNA-dependent RNA polymerase (RDRP) or the protease of the virus. The HCV protease [24] as well as the human protease DPP-4 [25], the coagulation Factor Xa [26] and thrombin [27] are serine proteases, while the angiotensin-converting enzyme (ACE) belongs to the metalloproteinase family [20,28]. As far as cleavage recognition motifs are concerned, the SARS-CoV-2 main protease cleaves the viral polyprotein at no less than 11 sites, recognizing the sequence Leu-Gln ↓ Ser/Ala/Gly [22]. The 3D structure of the SARS-CoV-2 main protease was compared with the
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