Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches

Song, Qiang; Xiong, Muya; Li, Jiameng; Hu, Hangchen; Su, Haijun; Xu, Yechun

doi:10.1039/d3sc00166k

Cited by 4 publications

(1 citation statement)

References 90 publications

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“…Multiple computational technologies, such as molecular dynamics (MD) simulations [ 25 , 26 , 27 , 28 , 29 , 30 ], calculations of binding free energies [ 31 , 32 , 33 , 34 ], principal component analysis, (PCA) [ 35 , 36 , 37 , 38 ] etc., play significant roles in investigating the atomic-level mechanism of binding between inhibitors and targets. Conventional MD simulations (cMD) are usually used to obtain conformational samplings of inhibitor–target complexes, but multiple separate MD (MSMD) simulations recently adopted by different work groups can reasonably improve the sampling efficiency of conformations [ 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies

et al. 2023

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β-amyloid cleaving enzyme 1 (BACE1) is regarded as an important target of drug design toward the treatment of Alzheimer’s disease (AD). In this study, three separate molecular dynamics (MD) simulations and calculations of binding free energies were carried out to comparatively determine the identification mechanism of BACE1 for three inhibitors, 60W, 954 and 60X. The analyses of MD trajectories indicated that the presence of three inhibitors influences the structural stability, flexibility and internal dynamics of BACE1. Binding free energies calculated by using solvated interaction energy (SIE) and molecular mechanics generalized Born surface area (MM-GBSA) methods reveal that the hydrophobic interactions provide decisive forces for inhibitor–BACE1 binding. The calculations of residue-based free energy decomposition suggest that the sidechains of residues L91, D93, S96, V130, Q134, W137, F169 and I179 play key roles in inhibitor–BACE1 binding, which provides a direction for future drug design toward the treatment of AD.

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Section: Introductionmentioning

confidence: 99%

Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies

et al. 2023

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Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape

Wu,

Go,

Nguyen

et al. 2024

Nat Commun

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Papain-like protease (PLpro) is an attractive drug target for SARS-CoV-2 because it is essential for viral replication, cleaving viral poly-proteins pp1a and pp1ab, and has de-ubiquitylation and de-ISGylation activities, affecting innate immune responses. We employ Deep Mutational Scanning to evaluate the mutational effects on PLpro enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify mutations in neighboring residues that alter activity. We characterize residues responsible for substrate binding and demonstrate that although residues in the blocking loop are remarkably tolerant to mutation, blocking loop flexibility is important for function. We additionally find a connected network of mutations affecting activity that extends far from the active site. We leverage our library to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.

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Mutational Profiling of SARS-CoV-2 PLpro in human cells reveals requirements for function, structure, and drug escape

Wu,

Go,

Nguyen

et al. 2024

Preprint

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SARS-CoV-2, the causative agent of COVID-19, is responsible for the recent global pandemic and remains a major source of mortality. Papain-like protease (PLpro) is a target for SARS-CoV-2 inhibitor development, as it is not only essential for viral replication through cleavage of the viral poly-proteins pp1a and pp1ab, but also has de-ubiquitylation and de-ISGylation activities, which can affect innate immune responses. To understand the features of PLpro that dictate activity and anticipate how emerging PLpro variants will affect function, we employed Deep Mutational Scanning to evaluate the mutational effects on enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify all mutations in neighboring residues that support or ablate activity. We characterize residues responsible for substrate binding and demonstrate that although the blocking loop is remarkably tolerant to nearly all mutations, its flexibility is important for enzymatic function. We additionally find a connected network of mutations affecting function but not structure that extends far from the active site. Using our DMS libraries we were able to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.

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Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches

Abstract: Papain-like protease (PLpro) is a promising therapeutic target against SARS-CoV-2, but its restricted S1/S2 subsites pose an obstacle in developing active site-directed inhibitors. We have recently identified C270 as a...

Cited by 4 publications

References 90 publications

Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies

Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies

Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape

Mutational Profiling of SARS-CoV-2 PLpro in human cells reveals requirements for function, structure, and drug escape

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