Optimization of norbornyl-based carbocyclic nucleoside analogs as cyclin-dependent kinase 2 inhibitors.,Journal of Molecular Recognition

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Optimization of norbornyl-based carbocyclic nucleoside analogs as cyclin-dependent kinase 2 inhibitors.
Journal of Molecular Recognition ( IF 2.3 ) Pub Date : 2020-03-25 , DOI: 10.1002/jmr.2842
Cemal Köprülüoğlu _{1,

2} , Milan Dejmek ₁ , Michal Šála ₁ , Haresh Ajani _{1,

2} , Hubert Hřebabecký ₁ , Jindřich Fanfrlík ₁ , Radek Jorda ₃ , Martin Dračínský ₁ , Eliška Procházková ₁ , Pavel Šácha ₁ , Vladimír Kryštof ₃ , Pavel Hobza _{1,

2} , Martin Lepšík ₁ , Radim Nencka ₁

Affiliation

We report on the discovery of norbornyl moiety as a novel structural motif for cyclin‐dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC₅₀ of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics‐based scoring was used to rationalize the affinities. In conclusion, the discovered 9‐hydroxymethylnorbornyl moiety was shown by joint experimental‐theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases.

中文翻译：

基于降冰片基的碳环核苷类似物作为细胞周期蛋白依赖性激酶 2 抑制剂的优化。

我们报告了降冰片基部分作为细胞周期蛋白依赖性激酶 2 (CDK2) 抑制剂的新型结构基序的发现，该基序是通过筛选碳环核苷类似物文库确定的。通过使用药物化学方法将三个微摩尔命中扩展为一系列 16 种新化合物。它们对 CDK2 具有显着的微摩尔活性，并且该系列中最好的化合物达到了 IC ₅₀190 纳米。通过建模和对接在分子细节中探索结合模式。使用基于量子力学的评分来合理化亲和力。总之，所发现的 9-羟甲基降冰片基部分通过联合实验-理论努力表明能够作为 CDK2 抑制剂的新取代基。这一发现为探索化学空间以寻找更有效的靶向这一类重要蛋白激酶的衍生物打开了大门。

更新日期：2020-03-25

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