Natural products and potent analogs: Capacity to interrupt the Spike-human ACE2 complex, Protease, and RdRp targets of COVID-19 replication via molecular docking and MD Simulations

Looking at the severity of SARS-CoV-2 even after the approval of several vaccines like Covishield and Covaxin, there is a concern to find a fruitful remedy for treating infected people in the whole world to stop the spreading of this virus. In this piece of work, we systematically carried out the computational study of potent natural flavonoids Podocarflavone A and Rugosaflavonoid A and their analogs with many targets of COVID-19 such as main Protease (6LU7), S-protein and human ACE2 receptor Complex (6VW1), and RdRp (6M71), which are essential for the survival of nCov-19. MD simulations for 50ns were carried out in TIP3P to check their stability. Thermodynamic stability of the receptor-ligand complexes was evaluated with MMGBSA, and MMPBSA study. The Podocarflavone A and dihydrorugosaflavonoid analogs showed effective binding energy (DS -8.8 to -8.0 Kcal/mol) with S-protein and human ACE2 receptor Complex (6VW1), Protease (6LU7), and RdRp (6M71) of COVID-19. The comparative analysis with several standard antivirals such as remdesivir, oseltamivir, lopinavir, sofosbuvir, tenofovir, galidesivir, and favipiravir displayed that these natural analogs can be better antiviral for the COVID-19. This study demonstrated that halogenated Podocarflavone 2b (MMGBSA -40.93 Kcal/mol, MMPBSA -14.16 Kcal/mol) has comparable results with lopinavir (MMGBSA -43.15 Kcal/mol, MMPBSA -11.89 Kcal/mol). These compounds could be selected for wet-lab screening to develop as lead molecules in the initial infective stage with spike protein and replicative stage with RdRp of the n-Cov-19 virus.