Fragment based discovery of arginine isosteres through REPLACE: towards non-ATP competitive CDK inhibitors.
Fragment based discovery of arginine isosteres through REPLACE: towards non-ATP competitive CDK inhibitors.
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DOI：
10.1016/j.bmc.2013.10.039
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发表时间：
2014-01-01
影响因子：
3.5
通讯作者：
McInnes C
中科院分区：
文献类型：
--
作者：
Premnath PN;Liu S;Perkins T;Abbott J;Anderson E;McInnes C
为了开发非ATP竞争性CDK 2/细胞周期蛋白A抑制剂，REPLACE策略已被应用于产生参与磷酸转移前底物募集的细胞周期蛋白结合基序（HAKRRLIF）的N-末端四肽的片段替代物。用于预测肽决定簇的小分子模拟物的对接方法通过再现已知抑制剂的实验结合模式进行了验证，并为评估与蛋白质-蛋白质相互作用位点的结合提供了有用的信息。除此之外，使用经验证的LigandFit对接方法预测的潜在精氨酸电子等排体使用固相合成连接至截短的C末端肽RLIF，并在竞争性结合测定中进行评价。测试后，鉴定的片段不仅代表关键精氨酸残基的适当模拟物，而且还与结合沟中存在的次要疏水口袋有效相互作用。对结合模式进行进一步评价以优化这些化合物的效力。通过在本研究中进一步应用REPLACE策略，鉴定了肽-小分子杂合CDK 2抑制剂，其更像药物并且适合作为抗肿瘤治疗剂进一步优化。
In order to develop non-ATP competitive CDK2/cyclin A inhibitors, the REPLACE strategy has been applied to generate fragment alternatives for the N-terminal tetrapeptide of the cyclin binding motif (HAKRRLIF) involved in substrate recruitment prior to phosphotransfer. The docking approach used for the prediction of small molecule mimics for peptide determinants was validated through reproduction of experimental binding modes of known inhibitors and provides useful information for evaluating binding to protein-protein interaction sites. Further to this, potential arginine isosteres predicted using the validated LigandFit docking method were ligated to the truncated C-terminal peptide, RLIF using solid phase synthesis and evaluated in a competitive binding assay. After testing, identified fragments were shown to represent not only appropriate mimics for a critical arginine residue but also to interact effectively with a minor hydrophobic pocket present in the binding groove. Further evaluation of binding modes was undertaken to optimize the potency of these compounds. Through further application of the REPLACE strategy in this study, peptide-small molecule hybrid CDK2 inhibitors were identified that are more drug-like and suitable for further optimization as anti-tumor therapeutics.
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影响因子：
7.3
作者：
Liu, Shu;Premnath, Padmavathy Nandha;McInnes, Campbell
通讯作者：
McInnes, Campbell
DOI：
10.2174/1568011033353506
发表时间：
2003-01-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
McInnes, Campbell;Andrews, Martin J. I.;Fischer, Peter M.
通讯作者：
Fischer, Peter M.
DOI：
10.1034/j.1399-3011.2002.21014.x
发表时间：
2002-11-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Zheleva, DI;McInnes, C;Lane, DP
通讯作者：
Lane, DP
影响因子：
2.9
作者：
Venkatachalam, CM;Jiang, X;Waldman, M
通讯作者：
Waldman, M
影响因子：
3.2
作者：
Andrews, MJI;McInnes, C;Fischer, PM
通讯作者：
Fischer, PM