Antimicrobial Alkaloids from Marine-Derived Fungi as Drug Leads versus COVID-19 Infection: A Computational Approach to Explore their Anti-COVID-19 Activity and ADMET Properties.
Sherouk Hussein SweilamMohammed H AlqarniFadia S YoussefPublished in: Evidence-based complementary and alternative medicine : eCAM (2022)
Therapeutic strategies based upon enzyme inhibition have recently gained higher attention in treating hazardous ailments. Herein, the potential use of seventy-two antimicrobial alkaloids isolated from marine-derived fungi to fight COVID-19 infection via inhibition of SARS-CoV-2 lethal virus was performed using in silico analyses. Molecular modelling was performed to assess their enzyme inhibitory potential on the main protease SARS-CoV-2 M Pro , 3-chymotrypsin-like protease SARS-CoV-2 3CL pro , and papain-like protease SARS-CoV-2 PL pro using Discovery Studio 4.5. Validation of the docking experiments was done by determination of RMSD (root mean square deviation) after redocking the superimposition of the cocrystalized ligands. Results showed that gymnastatin Z (72) showed the best fitting score in SARS-CoV-2 M Pro and SARS-CoV-2 3CL pr active sites with ∆G equal -34.15 and -34.28 Kcal/mol, respectively. Meanwhile, scalusamide C (62) displayed the highest fitting within SARS-CoV-2 PL pro active sites (∆ G = -26.91 Kcal/mol) followed by eutypellazine M (57) . ADMET/TOPKAT prediction displayed that eutypellazine M and scalusamide C showed better pharmacokinetic and pharmacodynamic properties. Gymnastatin Z is safer showing better toxicity criteria and higher rat oral LD 50 and rat chronic LOAEL (lowest observed adverse effect level). Chemometric analysis using principle component analysis (PCA) based on the binding energies observed for the compounds with respect to the three tested enzymes revealed the clustering of the compounds into different clusters. Eutypellazine M, scalusamide C, and gymnastatin Z appear in one cluster due to their closeness in activity. Thus, these compounds could serve as promising SARS-CoV-2 enzymes inhibitors that could help in alleviation of COVID-19 infection. Further investigations are recommended to confirm the results of molecular modelling.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- anti inflammatory
- oxidative stress
- staphylococcus aureus
- molecular docking
- small molecule
- working memory
- emergency department
- risk assessment
- single cell
- mass spectrometry
- molecular dynamics simulations
- high throughput
- dna binding
- drug induced
- climate change
- density functional theory