Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design

التفاصيل البيبلوغرافية
العنوان:	Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design
المؤلفون:	Choong, I. C., Lew, W., Lee, D., Pham, P., Burdett, M. T., Lam, J. W., Wiesmann, C., Luong, T. N., Fahr, B., DeLano, W. L., McDowell, R. S., Allen, D. A., Erlanson, D. A., Gordon, E. M., O'Brien, T.
المصدر:	Journal of Medicinal Chemistry; November 2002, Vol. 45 Issue: 23 p5005-5022, 18p
مستخلص:	The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S4 pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a Ki = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with Ki values in the 20−50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a Ki = 20 nM and selectivity of 8−500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4−8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.
قاعدة البيانات:	Supplemental Index

الوصف
تدمد:	00222623 15204804
DOI:	10.1021/jm020230j