Several variants of coronavirus 2 (SARS-CoV-2) have emerged from severe acute respiratory syndrome due to continuous genomic mutations. The World Health Organization (WHO) has classified these variants as variants of concern (VOC) and variants of interest (VOI) according to their virulence, rate of transmission, and ability to evade immune responses. Some common VOCs are Alpha, Beta, Gamma, Delta and Omicron.
Study: Computational studies demonstrated the potential of the steroid lactone to disrupt the surface interaction of the SARS-CoV-2 and hACE2 ear protein. Image credit: Sci Writers / Shutterstock
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SARS-CoV-2 contains four major structural proteins, namely spike (S), nucleocapsid (N), membrane (M), and envelope (E). It also contains nonstructural proteins, such as RNA-dependent proteases and RNA polymerases. The scientists reported that protein S, which is present as a crown-like tip on the outer surface of the virus, initiates viral infection in humans. The site of the receptor binding (RBD) domain of protein S binds to receptor 2 of the human angiotensin converting enzyme (hACE2-R) to initiate the pathogenesis process. The researchers revealed that the increase in SARS-CoV-2 virulence relative to SARS-CoV is due to a higher affinity for hACE2, caused by mutations in the S-RBD amino acid sequence.
Various strategies have been formulated to inhibit or decrease the affinity between S-RBD and ACE2, using small molecules, peptides, polyclonal / monoclonal antibodies, and so on. Some of these strategies have been less successful due to the continuous mutation of SARS-CoV-2 protein S. All available vaccines and therapeutics against coronavirus disease 2019 (COVID-19) have been developed from the S protein of the original SARS-CoV-2 strain. Therefore, these pharmaceutical approaches have shown reduced efficacy against some SARS-CoV-2 VOCs.
Plants are a potential source of several secondary metabolites used for drug formulation. Previous studies have shown that many herbs have antiviral properties and show minimal adverse effects. These studies have also reported that several Chinese drugs and herbs have significantly reduced clinical symptoms and reduced the mortality rate due to COVID-19. These natural medications could also improve mild flu symptoms.
Scientists claimed that computational methods, artificial intelligence and machine learning are important tools for discovering new drugs. This is because these methods have accelerated the selection of potent therapeutic molecules through high-throughput screening and have effectively reduced the cost of experiments.
Previous studies have reported that SLs are present in Withania spp, which has been a major source of modern medicine. These studies have shown that withanolides, a type of SL, possess many medicinal properties, such as cardiorespiratory, anticancer, mood-boosting, antioxidant, antiepileptic, hypochleplemic, diuretic, and hypoglycemic properties.
A new study
A previous in silico study has shown that withaferrin A has protease inhibitory properties. It is important to note that withaferrin A showed robust antiviral and immunomodulatory activity that could inhibit the major protease SARS-CoV-2 (Mpro). Scientists have stated that there are very few documents available on the antiviral effect of 4-Dehidrowithaferin A and Withalongolide A.
A new study published in Computers in Biology and Medicine has focused on identifying plant secondary metabolites (PSMs) that have a higher affinity for SARS-CoV-2 S-RBD. In this study, researchers have especially emphasized steroid lactones (SL), which can disrupt the early interaction between S-RBD and host ACE-2, using the method of molecular dynamic simulations (MDS). The scientists revealed that this method is more advantageous because it creates a probable native environment by simulating realistic conditions in which ligands interact with the target molecule.
In this study, researchers have used the Poisson-Boltzmann surface area of Molecular Mechanics (MMPBSA) for their analysis. A lower MMPBSA value infers a stable and energetically advantageous interaction, while a higher value is not as advantageous. In the current study, the researchers took advantage of this approach to select SL that could effectively disrupt the S-RBD and hACE2-R interaction.
Key findings
The researchers evaluated the potential of three SLs, namely 4-Dehydrowithaferin A, Withaferin A, and Withalongolide A, obtained from plant sources, to disrupt the S-RBD and hACE2-R interaction under two conditions (CON-I and CON -II), using the computational method mentioned above.
CON – I destabilized the interactions between S-RBD and hACE2-R by 4-Dehydrowithaferin A, which was inferred by measuring the increase in binding energy (BE). The researchers observed an increase in BE from -1028.5 kJ / mol (control) to -896.12 kJ / mol. They reported that 4-dehydrowithaferin A showed a strong interaction with S-RBD GLY496 with a hydrogen bond occupancy (HBO) of 37.33%.
In this study, the scientists reported that under CON-II, Withalongolide A had effectively disrupted all types of protein-protein interaction (PPI) of SARS-CoV-2 and hACE2-R S-RBD. This conclusion was based on the increase in BE from -913 kJ / mol (control) to -133.69 kJ / mol. In addition, the scientists reported a greater distance (> 3.55 nm) between the selected post-action review (AAR) combinations of S-RBD and hACE2-R. The authors revealed that Withalongolide A developed a hydrogen bond with S-RBD TYR453 (97%, HBO).
Conclusion
In this study, the authors revealed that SL molecules could effectively disrupt the S-RBD and hACE2-R interaction and prevent SARS-CoV-2 from recognizing host cells. The scientists claimed that these molecules could help design new COVID-19 therapeutics.