Identification and Validation of Human DNA Ligase Inhibitors Using Computer-Aided Drug Design

TLDR

DNA ligases are essential for DNA replication and repair, and because many cancer therapies induce DNA damage, there is growing interest in developing DNA repair inhibitors. The study aimed to identify inhibitors of human DNA ligase I using virtual screening and experimental testing. The authors targeted the DNA binding domain of hLigI, screening over one million compounds and selecting 192 for experimental evaluation. Ten compounds inhibited hLigI, five also suppressed cell proliferation; analysis showed that using multiple protein conformations and chemical clustering improves virtual screening, and the structurally diverse inhibitors possess drug‑like properties suitable for further development.

Abstract

Linking together of DNA strands by DNA ligases is essential for DNA replication and repair. Since many therapies used to treat cancer act by causing DNA damage, there is growing interest in the development of DNA repair inhibitors. Accordingly, virtual database screening and experimental evaluation were applied to identify inhibitors of human DNA ligase I (hLigI). When a DNA binding site within the DNA binding domain (DBD) of hLigI was targeted, more than 1 million compounds were screened from which 192 were chosen for experimental evaluation. In DNA joining assays, 10 compounds specifically inhibited hLigI, 5 of which also inhibited the proliferation of cultured human cell lines. Analysis of the 10 active compounds revealed the utility of including multiple protein conformations and chemical clustering in the virtual screening procedure. The identified ligase inhibitors are structurally diverse and have druglike physical and molecular characteristics making them ideal for further drug development studies.