Decoding the secrets: how conformational and structural regulators inhibit the human 20S proteasome

被引:1
作者
Fernandes, Pedro M. P. [1 ,2 ,3 ]
Guedes, Romina A. [1 ,2 ,3 ]
Victor, Bruno L. [4 ]
Salvador, Jorge A. R. [1 ,2 ]
Guedes, Rita C. [3 ]
机构
[1] Univ Coimbra, Fac Pharm, Lab Pharmaceut Chem, Coimbra, Portugal
[2] Univ Coimbra, Ctr Innovat Biomed & Biotechnol CIBB, Ctr Neurosci & Cell Biol CNC, Coimbra, Portugal
[3] Univ Lisbon, Res Inst Med IMed ULisboa, Fac Farm, Lisbon, Portugal
[4] Univ Lisbon, BioISI Biosyst & Integrat Sci Inst, Fac Sci, Lisbon, Portugal
来源
FRONTIERS IN CHEMISTRY | 2024年 / 11卷
关键词
20S proteasome inhibitors; drug resistance; mutations; molecular dynamics; molecular docking; PARTICLE MESH EWALD; BORTEZOMIB RESISTANCE; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; PROTEIN; PSMB5; MECHANISMS; CELLS; SUBSTRATE; UBIQUITIN;
D O I
10.3389/fchem.2023.1322628
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Acquired resistance to drugs that modulate specific protein functions, such as the human proteasome, presents a significant challenge in targeted therapies. This underscores the importance of devising new methodologies to predict drug binding and potential resistance due to specific protein mutations. In this work, we conducted an extensive computational analysis to ascertain the effects of selected mutations (Ala49Thr, Ala50Val, and Cys52Phe) within the active site of the human proteasome. Specifically, we sought to understand how these mutations might disrupt protein function either by altering protein stability or by impeding interactions with a clinical administered drug. Leveraging molecular dynamics simulations and molecular docking calculations, we assessed the effect of these mutations on protein stability and ligand affinity. Notably, our results indicate that the Cys52Phe mutation critically impacts protein-ligand binding, providing valuable insights into potential proteasome inhibitor resistance.
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页数:17
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