An in silico approach for identification of novel inhibitors as potential therapeutics targeting COVID-19 main protease.

Respiratory disease caused by a novel coronavirus, COVID-19, has been labeled a pandemic by the World Health Organization. Very little is known about the infection mechanism for this virus. More importantly, there are no drugs or vaccines that can cure or prevent a person from getting COVID-19. In this study, the binding affinity of 2692 protease inhibitor compounds that are known in the protein data bank, are calculated against the main protease of the novel coronavirus with docking and molecular dynamics (MD). Both the docking and MD methods predict the macrocyclic tissue factor-factor VIIa (PubChem ID: 118098670) inhibitor to bind strongly with the main protease with a binding affinity of -10.6 and -10.0 kcal/mol, respectively. The TF-FVIIa inhibitors are known to prevent the coagulation of blood and have antiviral activity as shown in the case of SARS coronavirus. Two more inhibitors, phenyltriazolinones (PubChem ID: 104161460) and allosteric HCV NS5B polymerase thumb pocket 2 (PubChem ID: 163632044) have shown antiviral activity and also have high affinity towards the main protease of COVID-19. Furthermore, these inhibitors interact with the catalytic dyad in the active site of the COVID-19 main protease that is especially important in viral replication. The calculated theoretical dissociation constants of the proposed COVID-19 inhibitors are found to be very similar to the experimental dissociation constant values of similar protease-inhibitor systems.Communicated by Ramaswamy H. Sarma.