tetano
Editor, Senior Moderator
J Biomol Struct Dyn
. 2020 Jul 17;1-21.
doi: 10.1080/07391102.2020.1792344. Online ahead of print.
Drug repurposing studies targeting SARS-CoV-2: an ensemble docking approach on drug target 3C-like protease (3CL [SUP]pro[/SUP])
Shruti Koulgi[SUP] 1 [/SUP], Vinod Jani[SUP] 1 [/SUP], Mallikarjunachari Uppuladinne[SUP] 1 [/SUP], Uddhavesh Sonavane[SUP] 1 [/SUP], Asheet Kumar Nath[SUP] 1 [/SUP], Hemant Darbari[SUP] 1 [/SUP], Rajendra Joshi[SUP] 1 [/SUP]
Affiliations
Abstract
The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome - novel Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-2003. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-CoV-2. The high-resolution crystal structure of the main protease of SARS-CoV-2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open-source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for the main protease helped in exploring the conformational variation in the drug-binding site of the main protease leading to the efficient binding of more relevant drug molecules. The drugs obtained as top hits from the ensemble docking possessed anti-bacterial and anti-viral properties. This in silico ensemble docking approach would support the identification of potential candidates for repurposing against COVID-19. Communicated by Ramaswamy H. Sarma.
Keywords: 3CLpro; COVID-19; SARS-CoV-2; cryptic pockets; main protease; repurposing.
. 2020 Jul 17;1-21.
doi: 10.1080/07391102.2020.1792344. Online ahead of print.
Drug repurposing studies targeting SARS-CoV-2: an ensemble docking approach on drug target 3C-like protease (3CL [SUP]pro[/SUP])
Shruti Koulgi[SUP] 1 [/SUP], Vinod Jani[SUP] 1 [/SUP], Mallikarjunachari Uppuladinne[SUP] 1 [/SUP], Uddhavesh Sonavane[SUP] 1 [/SUP], Asheet Kumar Nath[SUP] 1 [/SUP], Hemant Darbari[SUP] 1 [/SUP], Rajendra Joshi[SUP] 1 [/SUP]
Affiliations
- PMID: 32679006
- DOI: 10.1080/07391102.2020.1792344
Abstract
The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome - novel Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-2003. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-CoV-2. The high-resolution crystal structure of the main protease of SARS-CoV-2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open-source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for the main protease helped in exploring the conformational variation in the drug-binding site of the main protease leading to the efficient binding of more relevant drug molecules. The drugs obtained as top hits from the ensemble docking possessed anti-bacterial and anti-viral properties. This in silico ensemble docking approach would support the identification of potential candidates for repurposing against COVID-19. Communicated by Ramaswamy H. Sarma.
Keywords: 3CLpro; COVID-19; SARS-CoV-2; cryptic pockets; main protease; repurposing.