期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 16, 期 6, 页码 1716-1720出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2005.12.004
关键词
CDK2/cyclinA; protein-protein interaction inhibitor; guanidine replacement
The syntheses of potent small molecule inhibitors of the CDK2/cyclinA recruitment site are described. Structure-activity trends of nanomolar octapeptides were examined through amino-acid substitution and truncation of the sequence resulting in the identification of a smaller, albeit significantly less potent, tetrapeptide lead. These losses in affinity were recovered by side-chain optimization and by rigidification of the peptide backbone using a combination of solid-phase parallel synthesis and structure-based design. Finally, two guanidine functionalities were replaced to improve drug-like properties, resulting in neutral small molecules equal in activity to that of the peptide lead. (C) 2005 Elsevier Ltd. All rights reserved.
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