Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors

Mihalovits, Levente M.; Ferenczy, György G.; Keserü, György M.

doi:10.1016/j.csbj.2021.08.008

Cited by 5 publications

(3 citation statements)

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“…These results imply that Lys33 could be a proton acceptor and participates in the proton transfer process. It supports the widely accepted scenario that Lys33 initiates the reaction by deprotonating the Thr1 hydroxyl group. − …”

Section: Resultssupporting

confidence: 79%

“…This well-defined solvent molecule implied the general base function of Lys33. Although the β5-D17N mutant also provokes a severe defect in the enzyme activity, the role of Asp17 has not received its due importance. − Since then, most researchers recognized the importance of Lys33 and provided a unified view of the Thr1-Lys33 catalytic dyad for enzyme activity. Very recently, Serrano-Aparicio et al clarified the critical role of the Asp17-Lys33 dyad through the analysis of the electrostatic features of the active site of the 20S proteasome …”

Section: Introductionmentioning

confidence: 99%

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Elucidation of the α-Ketoamide Inhibition Mechanism: Revealing the Critical Role of the Electrostatic Reorganization Effect of Asp17 in the Active Site of the 20S Proteasome

Zhou,

Sang,

Wang

et al. 2023

ACS Catal.

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The 20S proteasome is an attractive drug target for the development of anticancer agents because it plays an important role in cellular protein degradation. It has a threonine residue that can act as a nucleophile to attack inhibitors with an electrophilic warhead, forming a covalent adduct. Fundamental understanding of the reaction mechanism between covalent inhibitors and the proteasome may assist the design and refinement of compounds with the desired activity. In this study, we investigated the covalent inhibition mechanism of an α-keto phenylamide inhibitor of the proteasome. We calculated the noncovalent binding free energy using the PDLD/S-LRA/β method and the reaction free energy through the empirical valence bond method (EVB). Several possible reaction pathways were explored. Subsequently, we validated the calculated activation and reaction free energies of the most plausible pathways by performing kinetic experiments. Furthermore, the effects of different ionization states of Asp17 on the activation energy at each step were also discussed. The results revealed that the ionization states of Asp17 remarkably affect the activation energies and there is an electrostatic reorganization of Asp17 during the course of the reaction. Our results demonstrate the critical electrostatic effect of Asp17 in the active site of the 20S proteasome.

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Section: Resultssupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Elucidation of the α-Ketoamide Inhibition Mechanism: Revealing the Critical Role of the Electrostatic Reorganization Effect of Asp17 in the Active Site of the 20S Proteasome

Zhou,

Sang,

Wang

et al. 2023

ACS Catal.

View full text Add to dashboard Cite

show abstract

“… 2 While many disciplines benefit from MD simulations, such as medicinal chemistry, 3 materials science, 4 biophysics, 5 or biochemistry, 6 this paper focuses mainly on the first one. MD is commonly used to examine specific events and properties on a molecular basis, most notably structural changes, 7 structural stability, 8 chemical reactions, 9 and dynamics of atomic-level phenomena. 4 Coupled with statistical thermodynamics, MD simulations are able to account for energies of simulation-related processes, as well.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations and Diversity Selection by Extended Continuous Similarity Indices

Rácz

Mihalovits

Bajusz

et al. 2022

J. Chem. Inf. Model.

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Molecular dynamics (MD) is a core methodology of molecular modeling and computational design for the study of the dynamics and temporal evolution of molecular systems. MD simulations have particularly benefited from the rapid increase of computational power that has characterized the past decades of computational chemical research, being the first method to be successfully migrated to the GPU infrastructure. While new-generation MD software is capable of delivering simulations on an ever-increasing scale, relatively less effort is invested in developing postprocessing methods that can keep up with the quickly expanding volumes of data that are being generated. Here, we introduce a new idea for sampling frames from large MD trajectories, based on the recently introduced framework of extended similarity indices. Our approach presents a new, linearly scaling alternative to the traditional approach of applying a clustering algorithm that usually scales as a quadratic function of the number of frames. When showcasing its usage on case studies with different system sizes and simulation lengths, we have registered speedups of up to 2 orders of magnitude, as compared to traditional clustering algorithms. The conformational diversity of the selected frames is also noticeably higher, which is a further advantage for certain applications, such as the selection of structural ensembles for ligand docking. The method is available open-source at .

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Targeting immunoproteasome in neurodegeneration: A glance to the future

Tundo

Cascio

Milardi

et al. 2023

Pharmacology & Therapeutics

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Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors

Abstract: Graphical abstract

Cited by 5 publications

References 50 publications

Elucidation of the α-Ketoamide Inhibition Mechanism: Revealing the Critical Role of the Electrostatic Reorganization Effect of Asp17 in the Active Site of the 20S Proteasome

Elucidation of the α-Ketoamide Inhibition Mechanism: Revealing the Critical Role of the Electrostatic Reorganization Effect of Asp17 in the Active Site of the 20S Proteasome

Molecular Dynamics Simulations and Diversity Selection by Extended Continuous Similarity Indices

Targeting immunoproteasome in neurodegeneration: A glance to the future

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