Targeting Allosteric Pockets of SARS-CoV-2 Main Protease Mpro

Repurposing of antivirals is an attractive therapeutic option for the treatment of COVID-19. M^pro (also called 3CL^pro) is a key protease of SARS-CoV-2 involved in viral replication, and is a promising drug target for testing the existing antivirals. A major challenge to test the efficacy of antivirals is the conformational plasticity of M^pro and its future mutation prone flexibility. To address this, we hereby propose combination therapy by drugging two specific additional pockets of M^pro probed in our studies. Long scale Molecular Dynamics (MD) simulations provide evidence of these additional sites being allosteric. Suitable choice of drugs in catalytic and allosteric pockets appear to be essential for combination therapy. Current study, based on docking and extensive set of MD simulations, finds the combination of Elbasvir, Glecaprevir, Ritonavir to be a viable candidate for further experimental drug testing/pharmacophore design for M^pro.