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revised on 21.09.2020 and posted on 21.09.2020by Khaled Abdel-Maksoud, Mohamed Ali al-Badri, Christian Lorenz, Jonathan W. Essex
The Coronavirus Disease of 2019 (COVID-19) is caused by a novel coronavirus known as the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research since the outset of the pandemic, definitive therapeutic agents for the treatment of the disease are yet to be identified. The main protease (MPro) of SARS-CoV-2 is an enzyme essential for virus replication through viral proteolytic activity and subsequent generation of infectious virus particles. Current computational efforts towards SARS-CoV-2 MPro inhibitor design have generally neglected an allosteric mechanism linked to His41-Cys145 catalytic dyad disruption and thus fail to target the open conformational state. We identify the rare event associated with the allosteric regulation of MPro activity in the orientation of the His41 imidazole side chain away from Cys145. In this work, we show that molecular dynamics and metadynamics simulations are fundamental for performing computer-aided MPro inhibitor design where the sampling of this allosteric mechanism within a computationally feasible timescale is essential. We calculate a 4.2 ± 1.9 kJ/mol free energy difference between the open and closed states of the SARS-CoV-2 MPro active site, indicating that favourable ligand interactions with His41 over the Cys145-His41 dyad interaction can stabilise the open state.