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

Mahmoud A El Hassab; Aly A Shoun; Sara T Al-Rashood; Tarfah Al-Warhi; Wagdy M Eldehna

doi:10.3389/fchem.2020.584894

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

Front Chem. 2020 Oct 30:8:584894. doi: 10.3389/fchem.2020.584894. eCollection 2020.

Authors

Mahmoud A El Hassab¹, Aly A Shoun², Sara T Al-Rashood³, Tarfah Al-Warhi⁴, Wagdy M Eldehna⁵

Affiliations

¹ Department of Pharmaceutical Chemistry, School of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt.
² Department of Microbiology and Immunology, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt.
³ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁴ Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.

Abstract

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.

Keywords: COVID-19; MM-PBSA calculations; fragment-based drug design; molecular dynamics; polymerase inhibitors.