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UBR5, an E3 ligase, is involved in the pathogenesis of various cancers, including breast, ovarian, and cervical cancers. As a pivotal proto-oncogene, UBR5 drives the degradation of crucial tumor suppressor genes, thereby facilitating oncogenesis. Despite its critical role, small molecule inhibitors targeting UBR5 have yet to be identified. This study aims to discover novel inhibitors for the UBR5 HECT domain through in-silico simulations. We used pocket prediction software to analyze UBR5 and its homologs, followed by consensus docking using AutoDock and GOLD on a curated set of known homolog inhibitors and an extensive DrugBank library. ADMET studies were used to further shortlist the compounds. Our comprehensive approach identified six novel inhibitors with significant binding potential, and also highlighted a promising binding pocket for heclin and its analogs. These findings provide a foundation for the development of new anti-cancer therapies, pending further experimental validation.

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Cancer Therapeutics: In-Silico Evaluation of Novel UBR5 Protein Inhibitors

  • 会议论文

  • 发表日期：

    2025年

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  • Maharshi Mukherjee,
  • Ngiam Lihong,
  • Chik Yan Kit David

摘要

UBR5, an E3 ligase, is involved in the pathogenesis of various cancers, including breast, ovarian, and cervical cancers. As a pivotal proto-oncogene, UBR5 drives the degradation of crucial tumor suppressor genes, thereby facilitating oncogenesis. Despite its critical role, small molecule inhibitors targeting UBR5 have yet to be identified. This study aims to discover novel inhibitors for the UBR5 HECT domain through in-silico simulations. We used pocket prediction software to analyze UBR5 and its homologs, followed by consensus docking using AutoDock and GOLD on a curated set of known homolog inhibitors and an extensive DrugBank library. ADMET studies were used to further shortlist the compounds. Our comprehensive approach identified six novel inhibitors with significant binding potential, and also highlighted a promising binding pocket for heclin and its analogs. These findings provide a foundation for the development of new anti-cancer therapies, pending further experimental validation.