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
Abstract
Recently, the world may never experience an outbreak like the coronavirus pandemic. Infections are increasing without reaching a peak. WHO has reported more than 14 million infections and nearly 600,000 confirmed deaths. Safety measures are insufficient and still no approved drugs for the COVID-19. Thus, it is necessary to develop a specific inhibitor for the COVID-19 infection. One of the most attractive targets in the virus life cycle is the polymerase enzyme responsible for the replication of virus genome. Here, we describe our Structure-Based Drug Design (SBDD) protocol for designing of a new potential inhibitor for COVID-19 polymerase. Firstly, the crystal structure of COVID-19 polymerase was retrieved from the protein data bank PDB ID (7bv2). Then, Fragment-Based Drug Design (FBDD) strategy was implemented using Discovery Studio 2016. The best five generated fragments were linked together using suitable carbon linkers to yield compound MAW-22. Thereafter, the strength of binding between compound MAW-22 and the COVID-19 polymerase was predicted by docking strategy using docking strategy. MAW-22 achieved high docking score, even more than the score achieved by Remdesivir indicating a 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 COVID-19 polymerase than Remdesivir. Also, it thought that this study had proved SBDD to be the most suitable way that could open a new era in future drug development for COVID-19 infection.