(1) Background: Main Protease (Mpro) is an attractive therapeutic target that acts in the replication and transcription of the SARS-CoV-2 coronavirus. Mpro is rich in residues exposed to protonation/deprotonation changes which could affect its enzymatic function. This work aimed to explore the effect of the protonation/deprotonation states of Mpro at different pHs using computational techniques. (2) Methods: The different distribution charges were obtained in all the evaluated pHs by the Semi-Grand Canonical Monte Carlo (SGCMC) method. A set of Molecular Dynamics (MD) simulations was performed to consider the different protonation/deprotonation during 250 ns, verifying the structural stability of Mpro at different pHs. (3) Results: The present findings demonstrate that active site residues and residues that allow Mpro dimerisation was not affected by pH changes. However, Mpro substrate-binding residues were altered at low pHs, allowing the increased pocket volume. Additionally, the results of the solvent distribution around S γ , H γ , N δ 1 and H δ 1 atoms of the catalytic residues Cys145 and His41 showed a low and high-water affinity at acidic pH, respectively. It which could be crucial in the catalytic mechanism of SARS-CoV-2 Mpro at low pHs. Moreover, we analysed the docking interactions of PF-00835231 from Pfizer in the preclinical phase, which shows excellent affinity with the Mpro at different pHs. (4) Conclusion: Overall, these findings indicate that SARS-CoV-2 Mpro is highly stable at acidic pH conditions, and this inhibitor could have a desirable function at this condition.
【저자키워드】 molecular dynamics, SARS-CoV-2 Mpro, docking analysis, pH, PF-00835231, 【초록키워드】 coronavirus, Dynamics, Transcription, docking, Replication, MPro, Pfizer, stability, inhibitor, distribution, change, mechanism, Interaction, therapeutic target, changes, Volume, residue, Cys145, His41, solvent, Affect, acidic pH, evaluated, was performed, analysed, not affected, conditions, catalytic, the SARS-CoV-2, 【제목키워드】 Dynamics, Simulation, Effect, the SARS-CoV-2,