Klebe Gerhard
Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg (Germany).
ChemMedChem. 2015 Feb;10(2):229-31. doi: 10.1002/cmdc.201402521. Epub 2014 Dec 23.
The prime property to rate the success of hit-to-lead-to-drug optimization in drug discovery is binding affinity. Rational approaches try to relate this property with structure. Affinity can be linked to the thermodynamic property, Gibbs free energy of binding, which itself factorizes into enthalpy and entropy. With respect to kinetic properties, affinity can be associated with the ratio of koff and kon of complex formation. Do these features help to obtain better insight into affinity? The present viewpoint assesses our current understanding of thermodynamics- or kinetics-structure relationships and questions the accuracy of data collected to learn about the thermodynamic and kinetic basis to comprehend affinity.
在药物发现中评估从命中到先导再到药物优化成功与否的首要属性是结合亲和力。合理的方法试图将此属性与结构联系起来。亲和力可以与热力学性质——结合的吉布斯自由能相关联，而吉布斯自由能本身又可分解为焓和熵。就动力学性质而言，亲和力可以与复合物形成的解离速率常数（koff）和结合速率常数（kon）的比值相关联。这些特征有助于更深入地理解亲和力吗？本文观点评估了我们目前对热力学或动力学与结构关系的理解，并质疑为了解亲和力的热力学和动力学基础而收集的数据的准确性。
