Potent β-lactam-based tyrosyl-DNA phosphodiesterase 1 inhibitors identified by a virtual screen.

ABSTRACT: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important therapeutic target. We recently reported several crystal structures of TDP1 with small molecules bound within the catalytic pocket. These molecules bind by forming hydrogen bonds with residues of the catalytic HKN motifs. Guided by these interactions, in our current work, we used the MolSoft ICM Pro suite of software to perform a virtual screen of the publicly available DrugBank 5.0 (3449 structures) for the ability to bind to the TDP1 catalytic pocket. Among compounds identified as giving good binding scores were several β-lactams. The β-lactam pharmacophore serves as a key component in a range of antibiotics. We subjected a subset of the β-lactam hits to gel-based TDP1 fluorescence catalytic assays and established that certain member

SUBMITTER: Zhao XZ 

PROVIDER: S-EPMC12280126 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature