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Handling Drug-Target Selectivity: A Study on Ureido Containing Carbonic Anhydrase Inhibitors
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-11-21 , DOI: 10.1016/j.ejmech.2020.113035
Ozlem Akgul , Srishti Singh , Jacob T. Andring , Robert McKenna , Silvia Selleri , Fabrizio Carta , Andrea Angeli , Claudiu T. Supuran

Here we report the synthesis of a series of taurine substituted sulfonamide derivatives 1-29 having the ureido moiety installed at the tail section as selective inhibitors of the tumor associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) IX and XII. The series was deeply investigated for their kinetic features which demonstrated a strong dependence on the ureido moiety. High resolution X-ray crystallographic investigation on selected ligand adducts complexed with hCA II and hCA IX-mimic revealed a strong correlation between the ureido moiety and the amino acid residues Q92 and Q67 in both the hCA II and hCA IX-mimic, contributing to highly stabilized ligand-protein complex.



中文翻译:

处理药物-目标选择性:含尿苷的碳酸酐酶抑制剂的研究

在这里我们报告了一系列的牛磺酸取代的磺酰胺衍生物1-29的合成,该衍生物具有安装在尾部的脲基部分,作为与肿瘤相关的人类(h)碳酸酐酶(CA; EC 4.2.1.1)IX和XII的选择性抑制剂。对该系列的动力学特征进行了深入研究,证实了其对脲基部分的强烈依赖性。对与hCA II和hCA IX模拟物络合的选定配体加合物进行的高分辨率X射线晶体学研究表明,在hCA II和hCA IX模拟物中,脲基部分与氨基酸残基Q92和Q67之间有很强的相关性,这有助于稳定的配体-蛋白质复合物。

更新日期:2020-11-22
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