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

preprint
revised on 26.08.2020 and posted on 26.08.2020 by Zahoor Ahmad Bhat, Dheeraj Chitara, Jawed Iqbal1, Sanjeev. B.S., Arumugam Madhumalar

Repurposing of antivirals is an attractive therapeutic option for the treatment of COVID-19. Mpro (also called 3CLpro) 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 Mpro and its future mutation prone flexibility. To address this, we hereby propose combination therapy by drugging two specific additional pockets of Mpro 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 Mpro.

History

Email Address of Submitting Author

amadhumalar@jmi.ac.in

Institution

Jamia Millia Islamia

Country

India

ORCID For Submitting Author

0000-0001-5314-7194

Declaration of Conflict of Interest

Authors have declared no conflict of interest.

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