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Screening, molecular simulation & in silico kinetics of virtually designed covid-19 main protease inhibitors
Mohammed S Aleissa1, Mohammed Al-Zharani1, Md Saquib Hasnain2
1Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia.
Abstract:
Coronavirus (covid-19) infection is considered to be deadliest ever pandemic experienced by the human being. It has very badly affected the socio-economic health of human and stuck the scientific community to think and rethink about its complete eradication. But due to no effective treatment or unavailability of vaccine the health professional could not show any significant improvement to control the pandemic. The situation needs newer molecule, vaccine or effective treatment to control covid-19 infection. Different target in viruses has been explored and proteases enzymes were found to be therapeutically effective target for the design of potential anti-covid-19 molecule as it plays the vital role in viral replication and assembly. Structure-based drug design was employed to discover the small molecule of anti-covid-19. Here we considered the small library of naturally occurring polyphenolic compounds and molecular docking, Molecular dynamics (MD) simulations, free binding energy calculation and in-silico ADME calculations to identify the newer HITs. Based upon their score the two molecules were identified as promising candidate. The docking scores were found to be -7.643 and -7.065 for the HIT1 and HIT-2 respectively. In MD simulations study the RMSD values were found to be 4.3 Å & 4.9 Å respectively. To validate these results MM-GBSA was performed and their binding free energies were computationally determined. The prime energy values of identified HITs (-13412.45 & -13441.8 kJ/mole) were found to be very close proximity to reference molecule (-13493.05 kJ/mole). Then in-silico ADME calculations were performed to calculate the drug likeliness identified HITs. BY considering all the values comparative to reference molecule and obtained in-silico pharmacokinetic properties of identified HITs we can suggest that HIT-1 and HIT-2 would be the most promising molecules that can inhibit the main protease enzyme of covid-19. These two molecules would become the potential drug candidate for the treatment of covid-19 infections.
Insights
Researchers identified two promising natural polyphenolic compounds (HIT-1 and HIT-2) as potential inhibitors of the main protease enzyme in coronavirus (COVID-19). These molecules show potential as drug candidates for treating COVID-19 infections.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Drug Discovery
Background:
- Coronavirus (COVID-19) poses a significant global health and economic challenge due to the lack of effective treatments and vaccines.
- Viral proteases are critical for replication and assembly, making them attractive therapeutic targets for antiviral drug design.
Purpose of the Study:
- To identify novel small molecules with potential anti-COVID-19 activity using structure-based drug design.
- To evaluate naturally occurring polyphenolic compounds as inhibitors of the main protease enzyme of COVID-19.
Main Methods:
- Structure-based drug design incorporating molecular docking, molecular dynamics (MD) simulations, and MM-GBSA for binding free energy calculations.
- In silico ADME calculations were performed to assess drug-likeness.
- A library of naturally occurring polyphenolic compounds was screened against the COVID-19 main protease.
Main Results:
- Two compounds, HIT-1 and HIT-2, were identified as promising candidates with significant docking scores (-7.643 and -7.065 kcal/mol, respectively).
- MD simulations showed stable interactions, and MM-GBSA calculations indicated binding free energies close to a reference molecule.
- In silico ADME predictions suggested favorable pharmacokinetic properties for HIT-1 and HIT-2.
Conclusions:
- HIT-1 and HIT-2 demonstrate significant potential as inhibitors of the COVID-19 main protease.
- These identified molecules represent promising drug candidates for the development of novel COVID-19 therapeutics.
