Version 1
: Received: 16 February 2020 / Approved: 17 February 2020 / Online: 17 February 2020 (07:28:31 CET)
Version 2
: Received: 27 February 2020 / Approved: 29 February 2020 / Online: 29 February 2020 (12:43:40 CET)
How to cite:
Chang, Y.; Tung, Y.; Lee, K.; Chen, T.; Hsiao, Y.; Chang, H.; Hsieh, T.; Su, C.; Wang, S.; Yu, J.; Shih, S.; Lin, Y.; Lin, Y.; Tu, Y.E.; Hsu, C.; Juan, H.; Tung, C.; Chen, C. Potential Therapeutic Agents for COVID-19 Based on the Analysis of Protease and RNA Polymerase Docking. Preprints.org2020, 2020020242. https://doi.org/10.20944/preprints202002.0242.v2.
Chang, Y.; Tung, Y.; Lee, K.; Chen, T.; Hsiao, Y.; Chang, H.; Hsieh, T.; Su, C.; Wang, S.; Yu, J.; Shih, S.; Lin, Y.; Lin, Y.; Tu, Y.E.; Hsu, C.; Juan, H.; Tung, C.; Chen, C. Potential Therapeutic Agents for COVID-19 Based on the Analysis of Protease and RNA Polymerase Docking. Preprints.org 2020, 2020020242. https://doi.org/10.20944/preprints202002.0242.v2.
Cite as:
Chang, Y.; Tung, Y.; Lee, K.; Chen, T.; Hsiao, Y.; Chang, H.; Hsieh, T.; Su, C.; Wang, S.; Yu, J.; Shih, S.; Lin, Y.; Lin, Y.; Tu, Y.E.; Hsu, C.; Juan, H.; Tung, C.; Chen, C. Potential Therapeutic Agents for COVID-19 Based on the Analysis of Protease and RNA Polymerase Docking. Preprints.org2020, 2020020242. https://doi.org/10.20944/preprints202002.0242.v2.
Chang, Y.; Tung, Y.; Lee, K.; Chen, T.; Hsiao, Y.; Chang, H.; Hsieh, T.; Su, C.; Wang, S.; Yu, J.; Shih, S.; Lin, Y.; Lin, Y.; Tu, Y.E.; Hsu, C.; Juan, H.; Tung, C.; Chen, C. Potential Therapeutic Agents for COVID-19 Based on the Analysis of Protease and RNA Polymerase Docking. Preprints.org 2020, 2020020242. https://doi.org/10.20944/preprints202002.0242.v2.
Abstract
The outbreak of novel coronavirus (COVID-19) infections in 2019 is in dire need of finding potential therapeutic agents. In this study, we used molecular docking to repurpose HIV protease inhibitors and nucleoside analogues for COVID-19, with evaluations based on docking scores calculated by AutoDock Vina and RosettaCommons. Our results suggest that Indinavir and Remdesivir possess the best docking scores, and comparison of the docking sites of the two drugs reveal a near perfect dock in the overlapping region of the protein pockets. After further investigation of the functional regions inferred from the proteins of SARS coronavirus, we discovered that Indinavir does not dock on any active sites of the protease, which may give rise to concern in regards to the efficacy of Indinavir. On the other hand, the docking site of Remdesivir is not compatible with any known functional regions, including template binding motifs, polymerization motifs and nucleoside triphosphate (NTP) binding motifs. However, when we tested the active form (CHEMBL2016761) of Remdesivir, the docking site revealed a perfect dock in the overlapping region of the NTP binding motif. This result suggests that Remdesivir could be a potential therapeutic agent. Clinical trials still must be done in order to confirm the curative effect of these drugs.
Keywords
COVID-19; molecular docking; HIV protease inhibitor; nucleotide analogues
Subject
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received:
29 February 2020
Commenter:
Chien-Yu Chen
Commenter's Conflict of Interests:
Author
Comment:
For the top-ranked protease inhibitor - Indinavir, we added one more experiment for protomer-Indinavir docking. However, we discovered that Indinavir does not dock on any active sites or dimerization sites of the protomer even though the docking site of Indinavir had an overlap with the dimerization site of protease, which may give rise to concern in regards to the efficacy of Indinavir.
For the top-ranked nucleoside analogue - Redemsivir, we further examined its different formations, including Remdesivir (Nucleoside Analogue Monophosphate Prodrug with Protect Group), GS441524 (Nucleoside Analogue) and CHEMBL2016761 (Nucleoside Analogue Triphosphate), since Redemsivir is a prodrug. The results showed that CHEMBL2016761, the active form of nucleoside analogues, which is activated by blocking viral replication, still has a good docking score. Moreover, the docking site of CHEMBL2016761 is perfectly located in the NTP binding motif, which suggested Redemsivir could be a potential therapeutic agent.
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Commenter: Chien-Yu Chen
Commenter's Conflict of Interests: Author
For the top-ranked nucleoside analogue - Redemsivir, we further examined its different formations, including Remdesivir (Nucleoside Analogue Monophosphate Prodrug with Protect Group), GS441524 (Nucleoside Analogue) and CHEMBL2016761 (Nucleoside Analogue Triphosphate), since Redemsivir is a prodrug. The results showed that CHEMBL2016761, the active form of nucleoside analogues, which is activated by blocking viral replication, still has a good docking score. Moreover, the docking site of CHEMBL2016761 is perfectly located in the NTP binding motif, which suggested Redemsivir could be a potential therapeutic agent.