Structure-Based Generation of a New Class of Potent Cdk4 Inhibitors: New de Novo Design Strategy and Library Design
| Autor: | Chinatsu Ikeura, Takashi Hayama, Hajime Morishima, Tetsuya Aoyama, Takumitsu Machida, Ikuko Suzuki-Takahashi, Toshiharu Iwama, Susumu Nishimura, Teruki Honma, Kyoko Hayashi, Kazuhiro Fukasawa, Noriaki Hashimoto, Mari Ikuta, Yoshikazu Iwasawa |
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| Rok vydání: | 2001 |
| Předmět: |
Models
Molecular Library design Scaffold Magnetic Resonance Spectroscopy Molecular model Pyridines Stereochemistry Design strategy Isoindoles Protein Serine-Threonine Kinases Crystallography X-Ray Structure-Activity Relationship Proto-Oncogene Proteins Drug Discovery CDC2-CDC28 Kinases Combinatorial Chemistry Techniques Urea Structure–activity relationship Homology modeling Enzyme Inhibitors Binding site Fluorenes Chemistry Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases Docking (molecular) Drug Design Molecular Medicine biological phenomena cell phenomena and immunity Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 44:4615-4627 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0103256 |
| Popis: | As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC(50) = 0.10 microM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC(50) = 0.042 microM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex. |
| Databáze: | OpenAIRE |
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