化学
基因亚型
碳酸酐酶
活动站点
立体化学
选择性
同工酶
合理设计
酶
结构-活动关系
药物设计
熵(时间箭头)
生物化学
体外
催化作用
基因
纳米技术
物理
量子力学
材料科学
作者
Audrius Zakšauskas,Edita Čapkauskaitė,Linas Jezepčikas,Vaida Linkuvienė,Miglė Kišonaitė,A. Smirnov,E. Manakova,S. Gražulis,Daumantas Matulis
标识
DOI:10.1016/j.ejmech.2018.06.059
摘要
Rational design of compounds that would bind specific pockets of the target proteins is a difficult task in drug design. The 12 isoforms of catalytically active human carbonic anhydrases (CAs) have highly similar active sites that make it difficult to design inhibitors selective for one or several CA isoforms. A series of CA inhibitors based on 2-chloro/bromo-benzenesulfonamide that is largely fixed in the CA active site together with one or two tails yielded compounds that were synthesized and evaluated as inhibitors of CA isoforms. Introduction of a second tail had significant influence on the binding affinity and two-tailed compounds in most cases provided high affinity and selectivity for CA IX and CA XIV. The contacts between several compounds and CA amino acids were determined by X-ray crystallography. Together with the intrinsic enthalpy and entropy of binding they provided the structure-thermodynamics correlations for this series of compounds with the insight how to rationally build compounds with desired CA isoform as a target.
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