Rey Arturo T. Fernandez | Mark Tristan J. Quimque | Kin Israel R. Notarte | Joe Anthony H. Manzano | Delfin Ynigo H. Pilapil | John Jeric P. San Jose | Omar A. Villalobos | Von De Leon | Allan Patrick G. Macebeo
The coronavirus disease 2019 (COVID-19) is a major public health concern caused by the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that resulted in a pandemic causing more than fifty million cases including approximately eight-thousand Filipino mortalities. In this study, we exploited the potential of secondary metabolites from Myxobacteria – a known producer of structurally and functionally diverse metabolites with broad-spectrum antiviral activity. Thus, the inhibitory prospects of 74 antiviral Myxobacterial secondary metabolites were assessed through in silico molecular interaction-based approaches against mechanisms underlying SARS-CoV-2 viral entry. Ligands were prepared using Avogadro and the three-dimensional structures of the proteins were derived from RCSB PDB. Virtual screening of the prepared library was performed following the Broyden-Fletcher-Goldfarb-Shanoo algorithm of AutoDock Vina and the binding affinity of the enzyme–ligand complex conformation was determined using UCSF Chimera, visualized, and analyzed using BIOVIA Discovery Studios. The 74 secondary metabolites were docked against the receptor-binding domains (RBDs) of the SARS-CoV-2 spike protein to angiotensin-converting enzyme 2 (ACE2) and glucose-regulated protein 78 (GRP78). Molecular dynamics simulations of the spike protein complex of SARS-CoV-2 were studied in YASARA dynamics software package with the aid of AMBER14 force field. SwissADME software and OSIRIS property explorer program were also used to predict in silico the pharmacokinetic and toxicity profile of the compounds, respectively. Among the metabolites screened, the chondramide group of metabolites – chondramide C3 and chondramide C9 – showed highest affinity to ACE2 (-8.6 kcal/mol) and GRP78 (-8.9 kcal/mol) RBD of the viral spike, respectively. Protein-protein docking experiments also showed repulsive interactions of inhibitor-spike protein complex with ACE2 and GRP78 receptors. Selectivity of chondramide C3 towards the ACE2 RBD of the spike was demonstrated by docking the ligand to ACE2 receptor itself. When the binding energies (BEs) of chondramide C3 towards ACE2 RBD (-8.6 kcal/mol) and ACE2 receptor (-7.6 kcal/mol) were compared, it displayed a stronger affinity towards the spike protein. The top fifteen strong binding Myxobacterial secondary metabolites were also docked against SARS-CoV-2 mutants A475V, L452R, V483A, and F490L wherein chondramide A9 consistently demonstrated high affinity towards each variant with a BE of -9.1 kcal/mol. These variants of the RBD of the spike to ACE2 exhibit resistance to neutralizing antibodies. The secondary metabolites were also screened to the globally prevalent mutation D614G of the spike protein with a co-occurring mutation, I472V, at the RBD of ACE2. Chondramide C emerged with the strongest BE towards the D614G-I472V variant at -8.5 kcal/mol. Molecular dynamics simulations demonstrated the stability of chondramides C, C3, and C9 when complexed with their target RBDs of the viral spike in a 120ns simulation. Finally, the top ligands were predicted to confer favorable pharmacokinetic and toxicity properties. Thus, Myxobacterial chondramides are promising compounds to develop drugs against SARS-COV-2 entry. and P. guajava have synergistic anticancer effects on lung cancer cells.
ISSN 2719-1990 (Print)
Philippine E-Journals
