Structure-Based Bioactive Phytochemical Design from Ayurvedic Formulations Towards Spike and Mpro Druggable Targets of SARS-CoV-2

The present COVID-19 global crisis invoked different disciplines of the biomedical research community to address the contagious human to human viral transmission and infection severity. Traditional or de novo drug discovery approach is a very time consuming process and will conflict with the urgency to discover new anti-viral drugs for combating the present global pandemic. Modern anti-viral drugs are not very effective and show resistance with serious adverse effects. Thus, identifying bioactive natural ingredients (phytochemical) from different medicinal plants or Ayurvedic formulations provides an effective alternative therapy for SARS-CoV-2 viral infections. We performed structure-based phytochemical design studies involving bioactive phytochemicals from medicinal plants towards two key druggable targets, spike glycoprotein and main protease (M^pro) of SARS-CoV-2. Phyllaemblicin class of phytocompounds showed better binding affinity towards both these SARS-CoV-2 targets and its binding mode revealed interactions with critical amino acid residues at its active sites. Also, we have successfully shown that the SARS-CoV-2 spike glycoprotein interaction towards human ACE2 receptor as its port of human cellular entry was blocked due to conformational variations in ACE2 receptor recognition by the binding of the phytocompound, Phyllaemblicin C at the ACE2 binding domain of spike protein. Our study shows that the Phyllaemblicin class of phytochemicals can be a potential dual inhibitor of spike and M^pro proteins of SARS-CoV-2 and could be promising for the treatment of COVID-19.