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

Abstract

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 LD₅₀ 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.

Figure 1

Diverse alkaloids identified from marine-derived fungal strains showing antimicrobial activities.

Figure 2

Diverse alkaloids identified from marine-derived fungal strains showing antimicrobial activities (cont'd).

Figure 3

Diverse alkaloids identified from marine-derived fungal strains showing antimicrobial activities (cont'd).

Figure 4

The ribbon structure of the three targeted proteins, SARS-CoV-2 M^Pro (a), SARS-CoV-2PL^pro, (b) and SARS-CoV-2 3CL^pro (c) downloaded from the protein data bank.

Figure 5

Validation of the docking experiments for SARS-CoV-2 M^Pro (a), SARS-CoV-2 PL^pro (b), and SARS-CoV-2 3CL^pro (c).

Figure 6

2D and 3D binding modes of the gymnastatin Z (72) in SARS-CoV-2 M^Pro (a), SARS-CoV-2PL^pro (b), and SARS-CoV-2 3CL^pr (c) active sites.

Figure 7

2D and 3D binding modes of the scalusamide C (62) in SARS-CoV-2 M^Pro (a), SARS-CoV-PL^pro (b), and SARS-CoV-2 3CL^pr (c) active sites.

Figure 8

2D and 3D binding modes of the eutypellazine M (57) in SARS-CoV-2 M^Pro (a), SARS-CoV-2 PL^pro (b), and SARS-CoV-2 3CL^pr (c) active sites.

Figure 9

2D and 3D binding modes of the respective ligands in SARS-CoV-2 M^Pro (a), SARS-CoV-2 PL^pro (b), and SARS-CoV-2 3CL^pr (c) active sites.

Figure 10

The presence of gymnastatin Z in the active pocket of SARS-CoV-2 M^Pro (a), SARS-CoV-2 PL^pro (b), and SARS-CoV-2 3CL^pr (c) active sites showing regions of hydrogen bond formation, hydrophobicity regions, and ionizable regions.

Figure 11

ADMET Plot for bioactive compounds, eutypellazine M (57), scalusamide C (62), and gymnastatin Z (72) and the cocrystalized ligands with the examined proteins showing the 95% and 99% confidence limit ellipses corresponding to the blood brain barrier (BBB) and the human intestinal absorption models; eutypellazine M (57), (triangle); scalusamide C (62) (filled square); and gymnastatin Z (72), (star) in ADMET_AlogP98.

Figure 12

PCA score plot performed based on the binding energies observed for the compounds with respect to the three tested proteins. Compounds are numbered as given in Table 1. The black arrow indicates the presence of eutypellazine M (57), scalusamide C (62), and gymnastatin Z (72) close to each other in a subcluster.