Boronic acid inhibitors of penicillin-binding protein 1b: serine and lysine labelling agents.

Autor:	Kollár L; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary.; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary., Grabrijan K; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia., Hrast Rambaher M; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia., Bozovičar K; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia., Imre T; MS Metabolomics Research Group, Research Centre for Natural Sciences, Budapest, Hungary., Ferenczy GG; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary., Gobec S; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia., Keserű GM; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary.; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary.
Jazyk:	angličtina
Zdroj:	Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2024 Dec; Vol. 39 (1), pp. 2305833. Date of Electronic Publication: 2024 Feb 27.
DOI:	10.1080/14756366.2024.2305833
Abstrakt:	Penicillin-binding proteins (PBPs) contribute to bacterial cell wall biosynthesis and are targets of antibacterial agents. Here, we investigated PBP1b inhibition by boronic acid derivatives. Chemical starting points were identified by structure-based virtual screening and aliphatic boronic acids were selected for further investigations. Structure-activity relationship studies focusing on the branching of the boron-connecting carbon and quantum mechanical/molecular mechanical simulations showed that reaction barrier free energies are compatible with fast reversible covalent binding and small or missing reaction free energies limit the inhibitory activity of the investigated boronic acid derivatives. Therefore, covalent labelling of the lysine residue of the catalytic dyad was also investigated. Compounds with a carbonyl warhead and an appropriately positioned boronic acid moiety were shown to inhibit and covalently label PBP1b. Reversible covalent labelling of the catalytic lysine by imine formation and the stabilisation of the imine by dative N-B bond is a new strategy for PBP1b inhibition.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu