Binding Kinetics Survey of the Drugged Kinome
Binding Kinetics Survey of the Drugged Kinome
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DOI：
10.1021/jacs.8b08048
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发表时间：
2018-11-21
影响因子：
15
通讯作者：
Fernandez-Montalvan, Amaury
中科院分区：
文献类型：
--
作者：
Georgi, Victoria;Schiele, Felix;Fernandez-Montalvan, Amaury
靶标停留时间作为药物发现中的重要优化参数而出现，然而靶标和脱靶接合动力学尚未与药物的临床性能明确地联系起来。在这里，我们开发了高通量结合动力学分析，以表征270种蛋白激酶抑制剂与40种临床相关靶标的相互作用。结果分析显示，结合率与亲和力的相关性优于解离率，并且缓慢解离的药物靶向复合物的分数从早期/临床前到晚期和FDA批准的化合物增加，表明每个参数对临床成功的不同贡献。结合参数与PK/ADME属性，我们说明了在计算机和细胞动力学选择性如何可以利用作为一种优化策略。此外，利用生物和化学信息学，我们发现了影响速率常数的结构特征。我们的研究结果强调了结合动力学信息在合理药物设计中的价值，并为今后的研究提供了资源。
Target residence time is emerging as an important optimization parameter in drug discovery, yet target and off-target engagement dynamics have not been clearly linked to the clinical performance of drugs. Here we developed high-throughput binding kinetics assays to characterize the interactions of 270 protein kinase inhibitors with 40 clinically relevant targets. Analysis of the results revealed that on-rates are better correlated with affinity than off-rates and that the fraction of slowly dissociating drug target complexes increases from early/preclinical to late stage and FDA-approved compounds, suggesting distinct contributions by each parameter to clinical success. Combining binding parameters with PK/ADME properties, we illustrate in silico and in cells how kinetic selectivity could be exploited as an optimization strategy. Furthermore, using bio- and chemoinformatics we uncovered structural features influencing rate constants. Our results underscore the value of binding kinetics information in rational drug design and provide a resource for future studies on this subject.