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ChemRxiv-_Myxobacteria.pdf (594.34 kB)

Myxobacterial Depsipeptide Chondramides Interrupt SARS-CoV-2 Entry by Targeting Its Broad, Cell Tropic Spike Protein: Antagonistic Prospects for Anti-COVID-19 Drug Discovery

preprint
submitted on 16.02.2021, 20:39 and posted on 17.02.2021, 13:22 by Rey Arturo T. Fernandez, Mark Tristan J. Quimque, Kin Israel Notarte, Joe Anthony Manzano, Delfin Yñigo H. Pilapil, Von Novi de Leon, John Jeric P. San Jose, Omar Villalobos, Allan Patrick Macabeo
The severity of the COVID-19 pandemic necessitated the search for drugs against the causative viral agent, SARS-CoV-2. Among the promising targets is the viral surface of SARS-CoV-2 adorned by spike proteins appearing as crown-like structures known for their function in viral attachment and entry mechanisms. To exploit the potential of previously reported antiviral microbial metabolites, we explored the antagonistic prospects of myxobacterial secondary metabolites against receptor-binding domains (RBD) to host cell receptors namely angiotensin-converting enzyme 2 (ACE2), basigin (CD147) and glucose-regulated protein 78 (GRP78) as well as the binding site of neuropilin-1 (NRP1) in the SARS-CoV-2 spike protein using in silico molecular interaction based approaches such as molecular and protein-protein docking along with an investigation of their pharmacokinetic profiles. Thus, the cyclic depsipeptide chondramides in general conferred high affinity and demonstrated strong binding to true viral hot spots in the spike protein such as Arg403, Gln493 and Gln498 with high selectivity compared to most of the host cell receptors studied. The binding energy (BE) of chondramide C3 (1), being the top ligand against ACE2 and CD147 RBD, remained relatively constant when docked against most of the spike variants such as A475V, L452R, V483A, S477N, F490L and V439K. On the other hand, the parent congener chondramide C (2) exhibited strong affinity against the UK variant (N501Y), the South African variant (E484K) and the globally prevalent D614G along with its co-occurring mutation in the RBD, I472V. Meanwhile, chondramide C6 (29) showed highest BE towards GRP78 RBD. To study the effect of complexed chondramide ligands, protein-protein binding experiments were carried out using high-ambiguity driven docking (HADDOCK) which showed weaker binding affinity between spike and the target host receptors. The in silico active chondramides in general conferred favourable pharmacokinetic properties illustrating their potential to be developed as anti-COVID-19 drugs that limit viral attachment and minimize infection.

History

Email Address of Submitting Author

kinotarte@gmail.com

Institution

University of Santo Tomas

Country

Philippines

ORCID For Submitting Author

0000-0002-6055-0886

Declaration of Conflict of Interest

The authors declare that they have no conflict of interests.

Version Notes

This is the first draft of the paper.

Exports