Identification of small-molecule binding sites of a ubiquitin-conjugating enzyme-UBE2T through fragment-based screening.

ABSTRACT: UBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin-conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug-like small molecules. Here, we performed fragment screening using ¹⁹ F-nuclear magnetic resonance (NMR) and validated the hits with ¹ H-¹⁵ N-heteronuclear single quantum coherence (HSQC) experiment and X-ray crystallographic studies. The cocrystal structures obtained revealed the binding modes of the hit fragments and allowed for the characterization of the fragment-binding sites. Further screening of structural analogues resulted in the identification of a compound series with inhi

SUBMITTER: Loh YY 

PROVIDER: S-EPMC10868430 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature