Identifying the specific-targeted marine cerebrosides against SARS-CoV-2: an integrated computational approach

Abstract

Cerebrosides are a group of metabolites belonging to the glycosphingolipids class of natural products. So far, 167 cerebrosides, compounds 1-167, have been isolated from diverse marine organisms or microorganisms. The as yet smaller number of compounds that have been studied more in depth proves a potential against challenging diseases, such as cancer, a range of viral and bacterial diseases, as well as inflammation. This review provides a comprehensive summary on this so far under-explored class of compounds, their chemical structures, bioactivities, and their marine sources, with a full coverage to the end of 2020. Today, the global pandemic concern, COVID-19, has claimed millions of death cases around the world, making the development of anti-SARS-CoV-2 drugs urgently needed for such a battle. Accordingly, selected examples from all subclasses of cerebrosides were virtually screened for potential inhibition of SARS-CoV-2 proteins that are crucially involved in the viral-host interaction, viral replication, or in disease progression. The results highlight five cerebrosides that could preferentially bind to the hACE2 protein, with binding scores between -7.1 and -7.6 kcal mol^-1 and with the docking poses determined underneath the first α₁-helix of the protein. Moreover, the molecular interaction determined by molecular dynamic (MD) simulation revealed that renieroside C1 (60) is more conveniently involved in key hydrophobic interactions with the best stability, least deviation, least ΔG (-6.9 kcal mol^-1) and an RMSD value of 3.6 Å. Thus, the structural insights assure better binding affinity and favorable molecular interaction of renieroside C1 (60) towards the hACE2 protein, which plays a crucial role in the biology and pathogenesis of SARS-CoV-2.

Fig. 1. Cerebrosides isolated from sponges (compounds 1–37); the configuration of the stereocenter in the side chain of 8, 9, and 25–27 was not indicated in the literature. Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 2. Cerebrosides isolated from sponges (compounds 40–51); the configuration of the stereocenters in the aglycon part of 50 and 51 was not given in the literature. Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 3. Cerebrosides isolated from sponges (compounds 52–74). Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 4. Cerebrosides isolated from sponges (compounds 75–81); the configurations at the flat-drawn stereocenters of 75, 76, 78, 79, and 81 were not presented in the literature.

Fig. 5. Cerebrosides isolated from star fish (compounds 82–104). Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 6. Cerebrosides isolated from star fish (compounds 105–123); the configuration at the stereocenter in the side chain of 119 and 120 was not established in the literature. Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 7. Cerebrosides isolated from a sea cumber (compounds 124–137); the configuration of the stereocenter in the side chain of structures 124–126, 128–132, and 135–137 was not published. Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 8. Cerebrosides isolated from Bryozoa and Ascidia (compounds 138–144); the configuration of the anomeric center of 138–141 was not given the literature. Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 9. Cerebrosides isolated from octocorals, sea urchins, and protists (compounds 146–152). Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 10. Cerebrosides isolated from marine-associated fungi (compounds 153–167). The configuration at the stereocenter in the aglycon part of 159 and 160 was not established in the literature. Green-colored compounds were selected for the molecular modeling experiments. The absolute configurations chosen for these structures are illustrated on them.

Fig. 11. Percentage of cerebrosides isolated from different genera of marine members (for the abbreviations: Eurotio. Eurotiomycetes, Thraust. Thraustochytrium, Dothid. Dothideomycetes, Hetero., Heterokontophyta).

Fig. 12. Biological activity spectrum of cerebrosides isolated from the studied marine organisms.

Fig. 13. Binding mode of top cerebrosides (represented as spheres) in the active site of hACE2 (green). The binding takes place under first α₁-helix responsible for recognizing viral S-protein (yellow). The interaction surface is shown and colored according to the electrostatic map of hACE2.

Fig. 14. Binding mode of 158 (pink) in hACE2 (green) is underneath the α₁-helix responsible for recognition of SARS-CoV-2 S-protein (yellow). Some residues at the interface are shown and labeled.

Fig. 15. RMSDs of top-scoring compounds inside the binding sites of ACE2 over 50 ns of MDS.

Fig. 16. RMSF values of protein–ligand complexes alongside the free protein.

Fig. 17. Protein–ligand contacts between the binding site of hACE-2 and compounds 52, 60, 158, 160, and 161 (A, B, C, D, and E, respectively).