DNA-encoded library screening on two validated enzymes of the peptidoglycan biosynthetic pathway. (1st October 2022)

• Record Type: Journal Article
• Authors: Proj, Matic; Bozovičar, Krištof; Hrast, Martina; Frlan, Rok; Gobec, Stanislav
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 73(2022)
• Publication Date: 2022-10-01
• Subjects: Ddl d-alanine:d-alanine ligase -- DEL DNA-encoded chemical library -- HTS high throughput screening -- MIC minimum inhibitory concentration -- MurA UDP-N-acetylglucosamine-enolpyruvyl transferase -- NAG N-acetylglucosamine -- NAM N-acetylmuramic acid; Antibacterial agents -- DNA-encoded library -- Screening -- Inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128915
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Screening of DNA-encoded libraries is an emerging technology for discovering hits against protein targets. With the recent launch of the DELopen platform, a facile screening of 4.4 billion compounds is available to accelerate the drug discovery process. Here we report an affinity-based screening of the DELopen library for the first time. The screening was performed against two bacterial enzymes of the peptidoglycan biosynthetic pathway, N -acetylglucosamine-enolpyruvyl transferase (MurA) and d -alanine:d -alanine ligase (DdlB). Several binders were obtained and selected for off-DNA synthesis. Hits with confirmed inhibitory potency were deconstructed into smaller fragments. In this way, two new MurA inhibitors with antibacterial activity were obtained and are available for further optimization.