Wang Ying, Edalji Rohinton P, Panchal Sanjay C, Sun Chaohong, Djuric Stevan W, Vasudevan Anil
AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
J Med Chem. 2017 Oct 26;60(20):8321-8335. doi: 10.1021/acs.jmedchem.7b00576. Epub 2017 Oct 5.
It is advocated that kinetic and thermodynamic profiling of bioactive compounds should be incorporated and utilized as complementary tools for hit and lead optimizations in drug discovery. To assess their applications in the EED hit-to-lead optimization process, large amount of thermodynamic and kinetic data were collected and analyzed via isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR), respectively. Slower dissociation rates (k) of the lead compounds were observed as the program progressed. Analysis of the kinetic data indicated that compound cellular activity correlated with both K and k. Our analysis revealed that ITC data should be interpreted in the context of chiral purity of the compounds. The thermodynamic signatures of the EED aminopyrrolidine compounds were found to be mainly enthalpy driven with improved enthalpic contributions as the program progressed. Our study also demonstrated that significant challenges still exist in utilizing kinetic and thermodynamic parameters for hit selection.
有人主张，生物活性化合物的动力学和热力学分析应作为药物发现中命中和先导优化的补充工具加以整合和利用。为了评估它们在EED命中到先导优化过程中的应用，分别通过等温滴定量热法（ITC）和表面等离子体共振（SPR）收集并分析了大量的热力学和动力学数据。随着项目的推进，观察到先导化合物的解离速率（k）较慢。动力学数据分析表明，化合物的细胞活性与K和k均相关。我们的分析表明，ITC数据应在手性纯度的背景下进行解释。发现EED氨基吡咯烷化合物的热力学特征主要由焓驱动，随着项目的推进，焓贡献有所改善。我们的研究还表明，在利用动力学和热力学参数进行命中选择方面仍然存在重大挑战。
