Mur ligases play an essential role in the biosynthesis of bacterial peptidoglycan and are therefore important targets for discovery of new antibacterial agents. We synthesised new sulfonamide inhibitors of MurD ligase, determined their mechanism of action and obtained the first crystal structure of MurD in complex with small-molecule inhibitors.These results provide so far the best starting point for structure-based design of new inhibitors of MurD as potential antibacterials. This achievement is a result of colaboration in EU project INTAFAR and with pharmaceutical industry (Lek).
COBISS.SI-ID: 4060698
Analysis of pharmacophores D-Phe-Pro-Arg of thrombin inhibitors and Arg-Gly-Asp of fibrinogen receptor antagonists inspired us to merge both pharmacophores or their mimetics in a single low molecular weight peptidomimetic compound which would inhibit thrombin and antagonize binding of fibrinogen to platelet fibrinogen receptor and thus possess anticoagulant and antiaggregatory activity. This innovative approach to antithrombotic drug discovery could lead to antithrombotic drugs of the future.
COBISS.SI-ID: 2371697
We prepared alkylphospholipid analogues of antitumour drugs perifosin and miltefosin with a nitroxide group at different positions in the alkyl chain. Biological testing revealed that one of the synthesized compounds showed significantly better inhibition of MCF-7 cell line than perifosin, whereas its high critical micellar conc. and low haemolytic activity indicated a more specific cytotoxic activity. The compound 4-/[/[13-(2-butyl-3-oxyl-4,4-dimethyl-1,3-oxazolidin-2-yl)tridecyl]oxy/(oxy)phosphoryl]oxy/-1,1-dimethylpiperidinium inner salt is thus an important molecular tool for EPR studies.
COBISS.SI-ID: 1808497
We have discovered a new type of powerful andselektivne trombin inhibitors with a central 1,4-benzoxazin-3(4H)-one scaffold. The most powerful inhibitor in the series, 3-(benzyl(2-(4-carbamimidoylbenzyl)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino)-3-oxopropanoic acid has a low nanomolarno inhibition constant for thrombin (Ki = 2.6 nM) and a very high selectivity against trypsin and factor Xa.
COBISS.SI-ID: 2286193
Based on their scientific expertise and international reputation, in the last 5 years team members published several review articles, related to the contents of the research programme, in leading icientific journals which i.a. describe a) Structure, function and design of i inhibitors of enzymes of cytoplasmatic steps of bacterial peptidoglycan biosynthesis. b) Design and synthesis of prodrugs of antithrombotic compounds incorporating a basic amidino group c) Application of Freidinger lactams in the design of peptidomimetics d) Survey of arginine mimicking structures
COBISS.SI-ID: 2249073