Immunomodulatory and anticytokine therapeutic potential of three Indian spices constituents and its hyaluronic acid conjugates for prevention and post COVID-19 complications: a computational modeling approach.

Abstract

Targeted drug delivery to SARS-CoV-2 host target proteins for preventing or blocking COVID-19 infection is making serious concern during COVID-19 pandemic and its consequent waves around the globe. People seek reliable, effective folkloric preventive medication for immediate and precautionary relief from COVID-19. These folkloric medicines were effective and saved many patients during the past COVID-19 pandemic. The current research study aims to deliver antiviral Indian spices phytocompounds and their hyaluronic acid conjugates to human host target proteins (ACE-2, TNF-α, IL-6, IL-1β, PAR-1) of SARS-CoV-2 to inhibit virus propagation and also to regulate early clinical complications of COVID-19. Targeted drug delivery of hyaluronic acid conjugated traditional natural bioactive agent produces more effective and fewer side effects in delivering novel drugs to human host proteins of COVID-19. In silico molecular docking study of six phytocompounds from three Indian spices and standard drug atazanavir and its hyaluronic acid conjugates reveals that phytocompounds and its hyaluronic acid conjugates possess high affinity to binding pockets of SARS-CoV-2 human host targets with more binding affinity scores. Most notably HA cyclocurcumin exhibit a docking score -9.9 kcal/mol against ACE-2 (PDB ID 1R42) target protein similarly HA-Hydrazinocurcumin exhibit a docking score -9.8 kcal/mol against PAR-1 (PDB ID 3VW7). ADMET validation of phytocompounds and their hyaluronic acid conjugates reveals its best pharmacokinetic profile over standard antiviral drug especially HA cyclocurcumin conjugate possesses high HIA (86%) and good pharmacokinetic profiles. DFT analysis affirms the reason behind the higher binding affinity of hyaluronic acid conjugates of spices phytocompounds towards all screened target proteins especially HA-hydrazinocurcumin conjugate possess high softness (19.1570 eV) and low hardness (0.0522 eV) values. Finally, MD simulation of best-docked compounds against ACE-2 and PAR-1 target protein revealed that hyaluronic acid conjugates of Indian spices compounds exhibit stable RMSD values and more protein-ligand interactions during simulation than hyaluronic acid conjugates of drug atazanavir.Communicated by Ramaswamy H. Sarma.