article · Frontiers in Chemistry
Targeting the RNA-dependent RNA polymerase enzyme responsible for viral genome replication offers a critical route for developing specific COVID-19 treatments. A structure-based computational drug design protocol was deployed to design a potential inhibitor against this enzyme using its crystal structure. Through fragment-based drug design, the five best fragments were connected with carbon linkers to generate a candidate molecule designated as MAW-22. Molecular docking studies indicated strong binding between MAW-22 and the target enzyme, producing a binding score higher than that of Remdesivir. Subsequent molecular dynamics simulation experiments conducted over 150 nanoseconds confirmed the stability and inhibitory potential of the compound relative to Remdesivir. The findings demonstrate the design of MAW-22 as a candidate inhibitor and highlight computational structure-based workflows as a promising avenue for developing targeted therapeutics against the virus.
The lack of approved specific therapies during the COVID-19 pandemic made discovering effective treatments an urgent global priority. By focusing on the polymerase enzyme essential for viral replication, computational drug design can rapidly screen and construct promising inhibitor molecules. Identifying candidate compounds such as MAW-22 provides initial molecular blueprints that could aid the development of more effective antiviral medications to combat infection.
This computational discovery offers a prospective lead compound, MAW-22, for pharmaceutical developers and medicinal chemists working on antiviral drug pipelines against COVID-19. As the findings are based entirely on in silico modelling, docking, and molecular dynamics simulations without laboratory synthesis or biological testing, the candidate remains at a very early stage of research. Substantial chemical synthesis, in vitro validation, and preclinical trials would be necessary before any therapeutic application can be realised.
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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 <b>MAW-22</b>. Thereafter, the strength of the binds between compound <b>MAW-22</b> and the SARS-COV-2 RNA-dependent RNA Polymerase was predicted by docking strategy using docking software. <b>MAW-22</b> achieved a high docking score, even more so than the score achieved by Remdesivir, indicating very strong binding between <b>MAW-22</b> 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 <b>MAW-22</b> 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.
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DOI: 10.3389/fchem.2020.584894
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