Macegoniuk Katarzyna, Kowalczyk Rafał, Rudzińska Anna, Psurski Mateusz, Wietrzyk Joanna, Berlicki Łukasz
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Bioorg Med Chem Lett. 2017 Mar 15;27(6):1346-1350. doi: 10.1016/j.bmcl.2017.02.022. Epub 2017 Feb 12.
Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in recent years, covalent urease inhibitors have been rarely investigated until now. Forty Michael acceptor-type compounds were screened for their inhibitory activities against bacterial urease, and several structures exhibited high potency in the nanomolar range. The correlation between chemical reactivity towards thiols and inhibitory potency indicated the most valuable compound - acetylenedicarboxylic acid, with K=42.5nM and logk=-2.14. Molecular modelling studies revealed that acetylenedicarboxylic acid is the first example of highly effective mode of binding based on simultaneous bonding to a cysteine residue and interaction with nickel ions present in the active site. Activity-reactivity profiling of reversible covalent enzyme inhibitors is a general method for the identification of valuable drug candidates.
共价酶抑制剂是一类非常重要的生物活性化合物，市场上有许多此类药物。尽管脲酶抑制剂的发现是近年来药物化学领域不断发展的一个方向，脲酶是一种对某些人类病原体的生存至关重要的尿素水解酶，但到目前为止，共价脲酶抑制剂很少被研究。筛选了40种迈克尔受体型化合物对细菌脲酶的抑制活性，几种结构在纳摩尔范围内表现出高效力。对硫醇的化学反应性与抑制效力之间的相关性表明，最有价值的化合物是乙炔二羧酸，K = 42.5 nM，logk = -2.14。分子建模研究表明，乙炔二羧酸是基于同时与半胱氨酸残基结合并与活性位点中存在的镍离子相互作用的高效结合模式的首个实例。可逆共价酶抑制剂的活性-反应性分析是鉴定有价值药物候选物的通用方法。
