Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations
(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 effec...
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| Autores principales: | , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/dbb96d94078d44d4b0c1278f7c43fb15 |
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| Sumario: | (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<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>, H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>, N<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>δ</mi></semantics></math></inline-formula>1 and H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>δ</mi></semantics></math></inline-formula>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. |
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