Drug Designing and Molecular Dynamics Identifies Cyanobacterial Nodularin-R as the Candidate Molecule Against SARS‒CoV‒2 Main Protease (Mpro)
Fahim Bashir*, Arif Bashir, Shabir Ahmad Ganai and Sayyed RZ*
ABSTRACT
The COVID-19 pandemic, caused by SARS-CoV-2, is a significant public health challenge. One approach to combat this virus is to develop antiviral drugs from natural products, such as those produced by cyanobacteria. Cyanobacteria produce a diverse range of secondary metabolites (SMs), including nodularin, aplysiatoxin, and obyanamide, which have unique chemical properties that make them potential scaffolds for drug development. We hypothesized that these SMs might be effective binders against the main protease of SARS CoV-2, a key target for antiviral therapy. To test this, we used structure-guided drug design tactics to investigate the binding affinity of 13 cyanobacterial SMs against the main protease. Our results showed that three metabolites - nodularin-R, aplysiatoxin, and obyanamide had the highest binding affinity towards the main protease. We further analyzed the interaction profiles of these molecules in a bound state with the main protease. Notably, we calculated the binding free energies of nodularin-R using molecular mechanics/generalized born surface area (MM-GBSA) and free energy landscape (FEL) analysis, along with molecular dynamics (MD) simulations. These simulations demonstrated the stability of nodularin-R in the active site of the main protease. Our study suggests that nodularin-R may be a promising therapeutic against SARS-CoV-2, pending further clinical evaluation. This research highlights the potential of cyanobacterial SMs as a rich source of antiviral compounds and demonstrates the power of structure-guided drug design in identifying promising leads.
