Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35037 Marburg, Germany.
F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
Biomolecules. 2020 Mar 27;10(4):509. doi: 10.3390/biom10040509.
The fluorination of lead-like compounds is a common tool in medicinal chemistry to alter molecular properties in various ways and with different goals. We herein present a detailed study of the binding of fluorinated benzenesulfonamides to human Carbonic Anhydrase II by complementing macromolecular X-ray crystallographic observations with thermodynamic and kinetic data collected with the novel method of kinITC. Our findings comprise so far unknown alternative binding modes in the crystalline state for some of the investigated compounds as well as complex thermodynamic and kinetic structure-activity relationships. They suggest that fluorination of the benzenesulfonamide core is especially advantageous in one position with respect to the kinetic signatures of binding and that a higher degree of fluorination does not necessarily provide for a higher affinity or more favorable kinetic binding profiles. Lastly, we propose a relationship between the kinetics of binding and ligand acidity based on a small set of compounds with similar substitution patterns.
将类似铅的化合物氟化是药物化学中常用的工具，可通过各种方式和不同的目标来改变分子性质。在此，我们通过补充大分子 X 射线晶体学观察结果以及使用新型 kinITC 方法收集的热力学和动力学数据，详细研究了氟化苯磺酰胺与人碳酸酐酶 II 的结合。我们的发现包括迄今为止在一些研究化合物的晶态中未知的替代结合模式，以及复杂的热力学和动力学结构-活性关系。它们表明，对于结合的动力学特征而言，苯磺酰胺核心的氟化在一个位置上特别有利，并且较高程度的氟化不一定提供更高的亲和力或更有利的动力学结合曲线。最后，我们基于具有相似取代模式的一小部分化合物提出了结合动力学与配体酸度之间的关系。
