Structural differences in 3C-like protease (Mpro) from SARS-CoV and SARS-CoV-2 : molecular insights revealed by Molecular Dynamics Simulations
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law..
Novel coronavirus SARS-CoV-2 has infected millions of people with thousands of mortalities globally. The main protease (Mpro) is vital in processing replicase polyproteins. Both the CoV's Mpro shares 97% identity, with 12 mutations, but none are present in the active site. Although many therapeutics and vaccines are available to combat SARS-CoV-2, these treatments may not be practical due to their high mutational rate. On the other hand, Mpro has a high degree of conservation throughout variants, making Mpro a stout drug target. Here, we report a detailed comparison of both the monomeric Mpro and the biologically active dimeric Mpro using MD simulation to understand the impact of the 12 divergent residues (T35V, A46S, S65N, L86V, R88K, S94A, H134F, K180N, L202V, A267S, T285A and I286L) on the molecular microenvironment and the interaction between crucial residues. The present study concluded that the change in the microenvironment of residues at the entrance (T25, T26, M49 and Q189), near the catalytic site (F140, H163, H164, M165 and H172) and in the substrate-binding site (V35, N65, K88 and N180) is due to 12 mutations in the SARS-CoV-2 Mpro. Furthermore, the involvement of F140, E166 and H172 residues in dimerization stabilizes the Mpro dimer, which should be considered. We anticipate that networks and microenvironment changes identified here might guide repurposing attempts and optimization of new Mpro inhibitors.
Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02089-6.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
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Zur Gesamtaufnahme - year:2022 |
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| Enthalten in: |
Structural chemistry - (2022) vom: 23. Nov., Seite 1-18 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Parmar, Meet [VerfasserIn] |
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| Links: |
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| Themen: |
3C-like proteases |
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Date Revised 16.02.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1007/s11224-022-02089-6 |
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| 520 | |a Novel coronavirus SARS-CoV-2 has infected millions of people with thousands of mortalities globally. The main protease (Mpro) is vital in processing replicase polyproteins. Both the CoV's Mpro shares 97% identity, with 12 mutations, but none are present in the active site. Although many therapeutics and vaccines are available to combat SARS-CoV-2, these treatments may not be practical due to their high mutational rate. On the other hand, Mpro has a high degree of conservation throughout variants, making Mpro a stout drug target. Here, we report a detailed comparison of both the monomeric Mpro and the biologically active dimeric Mpro using MD simulation to understand the impact of the 12 divergent residues (T35V, A46S, S65N, L86V, R88K, S94A, H134F, K180N, L202V, A267S, T285A and I286L) on the molecular microenvironment and the interaction between crucial residues. The present study concluded that the change in the microenvironment of residues at the entrance (T25, T26, M49 and Q189), near the catalytic site (F140, H163, H164, M165 and H172) and in the substrate-binding site (V35, N65, K88 and N180) is due to 12 mutations in the SARS-CoV-2 Mpro. Furthermore, the involvement of F140, E166 and H172 residues in dimerization stabilizes the Mpro dimer, which should be considered. We anticipate that networks and microenvironment changes identified here might guide repurposing attempts and optimization of new Mpro inhibitors | ||
| 520 | |a Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02089-6 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 3C-like proteases | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a Drug repurposing | |
| 650 | 4 | |a Molecular dynamics | |
| 650 | 4 | |a Mpro | |
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| 700 | 1 | |a Jha, Prakash C |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Dhaval |e verfasserin |4 aut | |
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