Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines

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• 作者：Michaela Hylsová ; ^a ; ¹ ; Benoit Carbain^a ; ^f ; ¹ ; Jindřich Fanfrlí ; k^b ; ¹ ; Lenka Musilová ; ^a ; Susanta Haldar^b ; ^c ; Cemal Kö ; prü ; lü ; oğlu^b ; ^c ; Haresh Ajani^b ; ^c ; Pathik S. Brahmkshatriya^b ; Radek Jorda^d ; Vladimí ; r Kry&scaron ; tof^d ; Pavel Hobza^b ; ^c ; Aude Echalier^e ; ² ; Kamil Paruch^a ; ^f ; ^{paruch@chemi.muni.cz} ; Martin Lep&scaron ; í ; k^b ; ^{lepsik@uochb.cas.cz}
• 关键词：Cyclin-dependent kinase 2 ; ATP-competitive type I inhibitors ; Pyrazolo[1 ; 5-a]pyrimidine ; Quantum mechanical scoring ; Protein-ligand binding ; Molecular dynamics ; Water thermodynamics ; X-ray crystal structure
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：27 January 2017
• 年：2017
• 卷：126
• 期：Complete
• 页码：1118-1128
• 全文大小：1617 K
• 卷排序：126

文摘

The importance of active-site water molecules in QM/COSMO scoring is demonstrated. 21 new pyrazolo[1,5-a]pyrimidine-based inhibitors of CDK 2 are synthesized. Crystal structure of active CDK2/cyclin A/inhibitor is reported.