Homology Model of the CDK1/cyclin B Complex |
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| Authors: | Connor F McGrath Nagarajan Pattabiraman Glen E Kellogg Thomas Lemcke Conrad Kunick Edward A Sausville |
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| Institution: | 1. Developmental Therapeutics Program Division of Cancer Treatment and Diagnosis , National Cancer Institute , Frederick , MD , 21702 , USA;2. Department of Oncology Lombardi Comprehensive Cancer Center , Georgetown University , 3970 Reservoir Road, NW Washington , DC , 20057 , U.S.A.;3. Department of Medicinal Chemistry , Institute for Structural Biology and Drug Discovery School of Pharmacy Virginia Commonwealth University , Richmond , VA , 23298 , U.S.A;4. Institut fuer Pharmazie Abteilung fuer Pharmazeutische Chemie Universitaet Hamburg , Bundesstrasse 45, D-20146 , Hamburg , Germany |
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| Abstract: | Abstract We describe a refined homology model of a CDK1/cyclin B complex that was previously used for the structure-based optimization of the Paullone class of inhibitors. The preliminary model was formed from the homologous regions of the deposited CDK2/cyclin A crystal structure. Further refinement of the CDK1/cyclin B complex was accomplished using molecular mechanics and hydropathic analysis with a protocol of constraints and local geometry searches. For the most part, our CKD1/cyclin B homology model is very similar to the high resolution CDK2/cyclin A crystal structure regarding secondary and tertiary features. However, minor discrepancies between the two kinase structures suggest the possibility that ligand design may be specifically tuned for either CDK1 or CDK2. Our examination of the CDK1/cyclin B model includes a comparison with the CDK2/cyclin A crystal structure in the PSTAIRE interface region, connecting portions to the ATP binding domain, as well as the ATP binding site itself. |
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| Keywords: | Homology modeling Structure-based drug design Molecular mechanics Hydropathic analysis Docking Protein 3D QSAR Cyclin dependent kinase inhibitors Paullones |
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