Vincent Madison dedicates this paper to the memory of Professor Elkan Blout. During my formative postdoctoral years, Elkan provided wise scientific counsel and warm personal encouragement. He created an environment that encouraged the development of creativity and independence while sharing the excitement of collaborative scientific discovery. Membership in the Blout group remains a cherished memory.
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Structure-guided discovery of cyclin-dependent kinase inhibitors
Article first published online: 15 OCT 2007
DOI: 10.1002/bip.20868
Copyright © 2008 Wiley Periodicals, Inc.
Issue
Biopolymers
Special Issue: This issue is dedicated to the memory of Elkan R. Blout, a founding editor of Biopolymers
Volume 89, Issue 5, pages 372–379, May 2008
Additional Information
How to Cite
Fischmann, T. O., Hruza, A., Duca, J. S., Ramanathan, L., Mayhood, T., Windsor, W. T., Le, H. V., Guzi, T. J., Dwyer, M. P., Paruch, K., Doll, R. J., Lees, E., Parry, D., Seghezzi, W. and Madison, V. (2008), Structure-guided discovery of cyclin-dependent kinase inhibitors. Biopolymers, 89: 372–379. doi: 10.1002/bip.20868
Publication History
- Issue published online: 28 FEB 2008
- Article first published online: 15 OCT 2007
- Manuscript Accepted: 5 OCT 2007
- Manuscript Revised: 1 OCT 2007
- Manuscript Received: 7 AUG 2007
- Abstract
- Article
- References
- Cited By
Keywords:
- crystal structures;
- CDK2 inhibitors;
- interaction energies
Abstract
CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 372–379, 2008.
This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com