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Structure-based virtual screening of novel USP5 inhibitors targeting the zinc finger ubiquitin-binding domain.
Wang, Tianhao; Tong, Jianbo; Zhang, Xing; Wang, Zhe; Xu, Lei; Pan, Peichen; Hou, Tingjun.
Afiliación
  • Wang T; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.
  • Tong J; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China. Electronic address: jianbotong@aliyun.com.
  • Zhang X; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.
  • Wang Z; School of Pharmacy, Hangzhou Normal University, Hangzhou, 310058, Zhejiang, PR China.
  • Xu L; Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, PR China.
  • Pan P; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China. Electronic address: panpeichen@zju.edu.cn.
  • Hou T; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China. Electronic address: tingjunhou@zju.edu.cn.
Comput Biol Med ; 174: 108397, 2024 May.
Article en En | MEDLINE | ID: mdl-38603896
ABSTRACT
The equilibrium of cellular protein levels is pivotal for maintaining normal physiological functions. USP5 belongs to the deubiquitination enzyme (DUBs) family, controlling protein degradation and preserving cellular protein homeostasis. Aberrant expression of USP5 is implicated in a variety of diseases, including cancer, neurodegenerative diseases, and inflammatory diseases. In this paper, a multi-level virtual screening (VS) approach was employed to target the zinc finger ubiquitin-binding domain (ZnF-UBD) of USP5, leading to the identification of a highly promising candidate compound 0456-0049. Molecular dynamics (MD) simulations were then employed to assess the stability of complex binding and predict hotspot residues in interactions. The results indicated that the candidate stably binds to the ZnF-UBD of USP5 through crucial interactions with residues ARG221, TRP209, GLY220, ASN207, TYR261, TYR259, and MET266. Binding free energy calculations, along with umbrella sampling (US) simulations, underscored a superior binding affinity of the candidate relative to known inhibitors. Moreover, US simulations revealed conformational changes of USP5 during ligand dissociation. These insights provide a valuable foundation for the development of novel inhibitors targeting USP5.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endopeptidasas / Dedos de Zinc Límite: Humans Idioma: En Revista: Comput Biol Med Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endopeptidasas / Dedos de Zinc Límite: Humans Idioma: En Revista: Comput Biol Med Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos