2023
DOI: 10.1039/d2sc06584c
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The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms

Abstract: The use of antiviral drugs can promote the appearance of mutations in the target protein that increase the resistance of the virus to the treatment. This is also the case...

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Cited by 18 publications
(39 citation statements)
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“…74 The CHARMM36 force-field 75 was used in the MM subsystems. Sizes of QM subsystems in these calculations were somewhat smaller than in the QM/MM optimization, but considerably larger than, for example, in previous studies [25][26][27] of the M Pro -nirmatrelvir reaction. We performed umbrella sampling simulations with additional harmonic potentials centered at different collective variable values.…”
Section: System Preparation and Computational Protocolsmentioning
confidence: 73%
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“…74 The CHARMM36 force-field 75 was used in the MM subsystems. Sizes of QM subsystems in these calculations were somewhat smaller than in the QM/MM optimization, but considerably larger than, for example, in previous studies [25][26][27] of the M Pro -nirmatrelvir reaction. We performed umbrella sampling simulations with additional harmonic potentials centered at different collective variable values.…”
Section: System Preparation and Computational Protocolsmentioning
confidence: 73%
“…In this case, the IP intermediate is not clearly visible on the free energy surface; the free energy profile at the step resembles the features reported by Ramos-Guzmán et al in modeling other reactions of covalent inhibition of M Pro . [24][25][26]34 In contrast, the MC intermediate corresponds to the minimum-energy structure in both the QM/MM and QM/MM MD calculations. We note that the nature of the Meisenheimer complex in the SNAr reactions 45,76,77 is still debated, in particular, whether it represents a reaction intermediate or a transition state.…”
Section: Reaction Of M Pro With X77cmentioning
confidence: 99%
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