6Q4A

CDK2 in complex with FragLite14

6Q4A の概要

• エントリーDOI: 10.2210/pdb6q4a/pdb
• 分子名称: CYCLIN-DEPENDENT KINASE 2, 5-iodanylpyrimidine (3 entities in total)
• 機能のキーワード: fragment, fraglite, cdk2, inhibitor, cell cycle
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34967.33

構造登録者

Wood, D.J.,Martin, M.P.,Noble, M.E.M. (登録日: 2018-12-05, 公開日: 2019-03-20, 最終更新日: 2024-01-24)

主引用文献

Wood, D.J.,Lopez-Fernandez, J.D.,Knight, L.E.,Al-Khawaldeh, I.,Gai, C.,Lin, S.,Martin, M.P.,Miller, D.C.,Cano, C.,Endicott, J.A.,Hardcastle, I.R.,Noble, M.E.M.,Waring, M.J.
FragLites-Minimal, Halogenated Fragments Displaying Pharmacophore Doublets. An Efficient Approach to Druggability Assessment and Hit Generation.
J.Med.Chem., 62:3741-3752, 2019

PubMed Abstract: Identifying ligand binding sites on proteins is a critical step in target-based drug discovery. Current approaches to this require resource-intensive screening of large libraries of lead-like or fragment molecules. Here, we describe an efficient and effective experimental approach to mapping interaction sites using a set of halogenated compounds expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites identify productive drug-like interactions, which are identified sensitively and unambiguously by X-ray crystallography, exploiting the anomalous scattering of the halogen substituent. This mapping of protein interaction surfaces provides an assessment of druggability and can identify efficient start points for the de novo design of hit molecules incorporating the interacting motifs. The approach is illustrated by mapping cyclin-dependent kinase 2, which successfully identifies orthosteric and allosteric sites. The hits were rapidly elaborated to develop efficient lead-like molecules. Hence, the approach provides a new method of identifying ligand sites, assessing tractability and discovering new leads.

PubMed: 30860382
DOI: 10.1021/acs.jmedchem.9b00304

実験手法

X-RAY DIFFRACTION (1.13 Å)