Optimization of Non-ATP Competitive CDK/Cyclin Groove Inhibitors through REPLACE-Mediated Fragment Assembly
Optimization of Non-ATP Competitive CDK/Cyclin Groove Inhibitors through REPLACE-Mediated Fragment Assembly
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DOI：
10.1021/jm3013882
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发表时间：
2013-02-28
影响因子：
7.3
通讯作者：
McInnes, Campbell
中科院分区：
文献类型：
--
作者：
Liu, Shu;Premnath, Padmavathy Nandha;McInnes, Campbell
药物发现的一个主要挑战是开发和改进靶向蛋白质-蛋白质相互作用的方法。关于REPLACE的更多信息（通过计算富集用部分配体替代物替换）策略用于产生蛋白质-蛋白质相互作用的抑制剂，表明其可用于优化关键决定簇的片段替代物，以有效的方式将这些片段替代物联合收割机组合，这是针对细胞周期蛋白依赖性激酶2（CDK 2）的化合物实现的。细胞周期蛋白调节亚基上的底物募集位点苯基杂环电子等排体取代了关键的电荷-电荷相互作用，为细胞周期蛋白沟的结合提供了新的结构见解。特别是，这些结果揭示了在N-末端封端肽的晶体结构中观察到的H-键的关键贡献。此外，模拟二肽相互作用的双（芳基）醚C-末端封端基团的结构-活性关系通过环取代进行探测，从而增加与主要疏水口袋的互补性。该研究进一步验证了REPLACE作为将肽化合物转化为更具药学相关性的化合物的有效策略。
A major challenge in drug discovery is to develop and improve methods for targeting protein-protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generating inhibitors of protein-protein interactions demonstrated that it can be used to optimize fragment alternatives of key determinants, to combine these in an effective way, and this was achieved for compounds targeting the cyclin-dependent kinase 2 (CDK2) substrate recruitment site on the cyclin regulatory subunit Phenylheterocyclic isosteres replacing a critical charge-charge interaction provided new structural insights for binding to the cyclin groove. In particular, these results shed light onto the key contributions of a H-bond observed in crystal structures of N-terminally capped peptides. Furthermore, the structure-activity relationship of a bis(aryl) ether C-terminal capping group mimicking dipeptide interactions was probed through ring substitutions, allowing increased complementarity with the primary hydrophobic pocket. This study further validates REPLACE as an effective strategy for converting peptidic compounds to more pharmaceutically relevant compounds.