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Investigating the Potential of 2-Ethylbutyl-(Phenoxy)phosphoryl-D-Alaninate Against RNA-Dependent RNA Polymerase
Sandeep Yadav1, Durgesh Kumar2, Haritma Chopra2
1Department of Chemistry, ARSD College, University of Delhi, New Delhi, India.
Abstract:
There was an emergency call globally when COVID-19 was detected in December 2019. The SARS-CoV-2 virus, a modified virus, causes this contagious disease. Although research is being conducted throughout the world, the main target is still to find the promising candidate to target RNA-dependent RNA polymerase (RdRp) to provide possible drug against COVID-19. Aim of this work is to find a molecule to inhibit the translational process of viral protein synthesis. Density Functional Theory calculations revealed information about the formation of the desired ligand (RD). Molecular docking of RD with RdRp was performed and compared with some reported molecules and the data revealed that RD had the best docking score with RdRp (-6.7 kcal/mol). Further, molecular dynamics (MD) simulations of RD with RdRp of SARS-CoV-2 revealed the formation of stable complex with a maximum number of seven hydrogen bonds. Root mean square deviations values are in acceptable range and root mean square fluctuations are also low, indicating stable complex formation. Further, based on MM-GBSA calculation, RD formed a stable complex with RdRp of nCoV with ΔG° of -12.28 kcal mol-1.
Insights
Researchers identified a novel molecule, RD, that effectively inhibits the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). This promising drug candidate shows stable complex formation, offering a potential new treatment for COVID-19.
Area of Science:
- Computational chemistry
- Drug discovery
- Virology
Background:
- COVID-19, caused by SARS-CoV-2, emerged in December 2019, necessitating urgent therapeutic strategies.
- Targeting the viral RNA-dependent RNA polymerase (RdRp) is a key approach for developing COVID-19 drugs.
- Inhibiting viral protein synthesis is crucial for controlling SARS-CoV-2 replication.
Purpose of the Study:
- To identify a novel molecule capable of inhibiting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).
- To evaluate the potential of the identified molecule as a therapeutic agent against COVID-19 by assessing its binding affinity and complex stability.
Main Methods:
- Density Functional Theory (DFT) calculations were used to characterize the potential drug molecule (RD).
- Molecular docking simulations were performed to assess the binding affinity of RD with SARS-CoV-2 RdRp.
- Molecular dynamics (MD) simulations and MM-GBSA calculations were employed to analyze the stability of the RD-RdRp complex.
Main Results:
- DFT calculations confirmed the formation of the desired ligand, RD.
- Molecular docking revealed that RD exhibited the highest binding score (-6.7 kcal/mol) with RdRp compared to other molecules.
- MD simulations and MM-GBSA calculations demonstrated a stable complex formation between RD and SARS-CoV-2 RdRp, with a maximum of seven hydrogen bonds and a binding free energy (ΔG°) of -12.28 kcal/mol.
Conclusions:
- The identified molecule, RD, shows significant potential as an inhibitor of SARS-CoV-2 RdRp.
- The stable complex formed between RD and RdRp suggests its efficacy as a possible antiviral drug candidate.
- Further research into RD could lead to a new therapeutic option for treating COVID-19.
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