Identification of a New Potential SARS-COV-2 RNA-Dependent RNA Polymerase Inhibitor via Combining Fragment-Based Drug Design, Docking, Molecular Dynamics, and MM-PBSA Calculations
The world has recently been struck by the SARS-Cov-2 pandemic, a situation that people have never before experienced. Infections are increasing without reaching a peak. The WHO has reported more than 25 million infections and nearly 857,766 confirmed deaths. Safety measures are insufficient and ther...
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2020.584894/full |
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doaj-9ed1753acf284447bd8801d0a8c6aa8e2020-11-25T04:02:10ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462020-10-01810.3389/fchem.2020.584894584894Identification of a New Potential SARS-COV-2 RNA-Dependent RNA Polymerase Inhibitor via Combining Fragment-Based Drug Design, Docking, Molecular Dynamics, and MM-PBSA CalculationsMahmoud A. El Hassab0Aly A. Shoun1Sara T. Al-Rashood2Tarfah Al-Warhi3Wagdy M. Eldehna4Department of Pharmaceutical Chemistry, School of Pharmacy, Badr University in Cairo (BUC), Cairo, EgyptDepartment of Microbiology and Immunology, Faculty of Pharmacy, Damanhour University, Damanhour, EgyptDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaDepartment of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, EgyptThe world has recently been struck by the SARS-Cov-2 pandemic, a situation that people have never before experienced. Infections are increasing without reaching a peak. The WHO has reported more than 25 million infections and nearly 857,766 confirmed deaths. Safety measures are insufficient and there are still no approved drugs for the COVID-19 disease. Thus, it is an urgent necessity to develop a specific inhibitor for COVID-19. One of the most attractive targets in the virus life cycle is the polymerase enzyme responsible for the replication of the virus genome. Here, we describe our Structure-Based Drug Design (SBDD) protocol for designing of a new potential inhibitor for SARS-COV-2 RNA-dependent RNA Polymerase. Firstly, the crystal structure of the enzyme was retrieved from the protein data bank PDB ID (7bv2). Then, Fragment-Based Drug Design (FBDD) strategy was implemented using Discovery Studio 2016. The five best generated fragments were linked together using suitable carbon linkers to yield compound MAW-22. Thereafter, the strength of the binds between compound MAW-22 and the SARS-COV-2 RNA-dependent RNA Polymerase was predicted by docking strategy using docking software. MAW-22 achieved a high docking score, even more so than the score achieved by Remdesivir, indicating very strong binding between MAW-22 and its target. Finally, three molecular dynamic simulation experiments were performed for 150 ns to validate our concept of design. The three experiments revealed that MAW-22 has a great potentiality to inhibit the SARS-COV-2 RNA-dependent RNA Polymerase compared to Remdesivir. Also, it is thought that this study has proven SBDD to be the most suitable avenue for future drug development for the COVID-19 infection.https://www.frontiersin.org/articles/10.3389/fchem.2020.584894/fullCOVID-19polymerase inhibitorsfragment-based drug designmolecular dynamicsMM-PBSA calculations |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Mahmoud A. El Hassab Aly A. Shoun Sara T. Al-Rashood Tarfah Al-Warhi Wagdy M. Eldehna |
| spellingShingle |
Mahmoud A. El Hassab Aly A. Shoun Sara T. Al-Rashood Tarfah Al-Warhi Wagdy M. Eldehna Identification of a New Potential SARS-COV-2 RNA-Dependent RNA Polymerase Inhibitor via Combining Fragment-Based Drug Design, Docking, Molecular Dynamics, and MM-PBSA Calculations Frontiers in Chemistry COVID-19 polymerase inhibitors fragment-based drug design molecular dynamics MM-PBSA calculations |
| author_facet |
Mahmoud A. El Hassab Aly A. Shoun Sara T. Al-Rashood Tarfah Al-Warhi Wagdy M. Eldehna |
| author_sort |
Mahmoud A. El Hassab |
| title |
Identification of a New Potential SARS-COV-2 RNA-Dependent RNA Polymerase Inhibitor via Combining Fragment-Based Drug Design, Docking, Molecular Dynamics, and MM-PBSA Calculations |
| title_short |
Identification of a New Potential SARS-COV-2 RNA-Dependent RNA Polymerase Inhibitor via Combining Fragment-Based Drug Design, Docking, Molecular Dynamics, and MM-PBSA Calculations |
| title_full |
Identification of a New Potential SARS-COV-2 RNA-Dependent RNA Polymerase Inhibitor via Combining Fragment-Based Drug Design, Docking, Molecular Dynamics, and MM-PBSA Calculations |
| title_fullStr |
Identification of a New Potential SARS-COV-2 RNA-Dependent RNA Polymerase Inhibitor via Combining Fragment-Based Drug Design, Docking, Molecular Dynamics, and MM-PBSA Calculations |
| title_full_unstemmed |
Identification of a New Potential SARS-COV-2 RNA-Dependent RNA Polymerase Inhibitor via Combining Fragment-Based Drug Design, Docking, Molecular Dynamics, and MM-PBSA Calculations |
| title_sort |
identification of a new potential sars-cov-2 rna-dependent rna polymerase inhibitor via combining fragment-based drug design, docking, molecular dynamics, and mm-pbsa calculations |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Chemistry |
| issn |
2296-2646 |
| publishDate |
2020-10-01 |
| description |
The world has recently been struck by the SARS-Cov-2 pandemic, a situation that people have never before experienced. Infections are increasing without reaching a peak. The WHO has reported more than 25 million infections and nearly 857,766 confirmed deaths. Safety measures are insufficient and there are still no approved drugs for the COVID-19 disease. Thus, it is an urgent necessity to develop a specific inhibitor for COVID-19. One of the most attractive targets in the virus life cycle is the polymerase enzyme responsible for the replication of the virus genome. Here, we describe our Structure-Based Drug Design (SBDD) protocol for designing of a new potential inhibitor for SARS-COV-2 RNA-dependent RNA Polymerase. Firstly, the crystal structure of the enzyme was retrieved from the protein data bank PDB ID (7bv2). Then, Fragment-Based Drug Design (FBDD) strategy was implemented using Discovery Studio 2016. The five best generated fragments were linked together using suitable carbon linkers to yield compound MAW-22. Thereafter, the strength of the binds between compound MAW-22 and the SARS-COV-2 RNA-dependent RNA Polymerase was predicted by docking strategy using docking software. MAW-22 achieved a high docking score, even more so than the score achieved by Remdesivir, indicating very strong binding between MAW-22 and its target. Finally, three molecular dynamic simulation experiments were performed for 150 ns to validate our concept of design. The three experiments revealed that MAW-22 has a great potentiality to inhibit the SARS-COV-2 RNA-dependent RNA Polymerase compared to Remdesivir. Also, it is thought that this study has proven SBDD to be the most suitable avenue for future drug development for the COVID-19 infection. |
| topic |
COVID-19 polymerase inhibitors fragment-based drug design molecular dynamics MM-PBSA calculations |
| url |
https://www.frontiersin.org/articles/10.3389/fchem.2020.584894/full |
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