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利用虚拟筛选以及初步的、基于结构的先导物范围界定，发现一种具有新型结合模式的强效CDK2抑制剂。

Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping.

作者信息

Richardson Christine M, Nunns Claire L, Williamson Douglas S, Parratt Martin J, Dokurno Pawel, Howes Rob, Borgognoni Jenifer, Drysdale Martin J, Finch Harry, Hubbard Roderick E, Jackson Philip S, Kierstan Peter, Lentzen Georg, Moore Jonathan D, Murray James B, Simmonite Heather, Surgenor Allan E, Torrance Christopher J

机构信息

Vernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK.

出版信息

Bioorg Med Chem Lett. 2007 Jul 15;17(14):3880-5. doi: 10.1016/j.bmcl.2007.04.110. Epub 2007 May 6.

DOI:10.1016/j.bmcl.2007.04.110
PMID:17570665
Abstract

Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.

摘要

针对pCDK2/细胞周期蛋白A晶体结构进行虚拟筛选，从而鉴定出一种强效且新颖的CDK2抑制剂，该抑制剂与激酶结合基序呈现出不同寻常的相互作用模式。借助X射线晶体学和建模技术，实施了一种药物化学策略，以探究晶体结构中观察到的相互作用并建立构效关系。还考虑了基于片段的方法，但观察到一种不同的、更传统的结合模式。使用合理设计策略提高了化合物对GSK-3β的选择性，并通过晶体学验证了CDK2的结合模式。

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