Impact of linker strain and flexibility in the design of a fragment-based inhibitor.
Impact of linker strain and flexibility in the design of a fragment-based inhibitor.
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DOI：
10.1038/nchembio.163
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发表时间：
2009-06
影响因子：
14.8
通讯作者：
Stivers, James T.
中科院分区：
文献类型：
--
作者：
Chung, Suhman;Parker, Jared B.;Bianchet, Mario;Amzel, L. Mario;Stivers, James T.
将与酶上相邻位点结合的分子片段连接在一起可以产生高亲和力抑制剂。理想地，该策略将采用不干扰片段的最佳结合几何形状并且不具有将增加结合的熵罚的过度构象柔性的接头。实际上，由于连接体化学的限制，这些目标很少实现。在这里，我们系统地探讨了能量和结构的影响，刚性和柔性连接的结合片段为基础的抑制剂的人尿嘧啶DNA糖基化酶。结合自由能与共晶结构的分析表明，给定接头的柔性和应变可以对结合亲和力产生显著影响，即使当结合片段被最佳定位时。这样的效果是不明显的结构检查，并强调了在基于片段的药物发现工作中的接头优化的重要性。
The linking together of molecular fragments that bind to adjacent sites on an enzyme can lead to high affinity inhibitors. Ideally, this strategy would employ linkers that do not perturb the optimal binding geometries of the fragments and do not have excessive conformational flexibility that would increase the entropic penalty of binding. In reality, these aims are seldom realized due to limitations in linker chemistry. Here we systematically explore the energetic and structural effects of rigid and flexible linkers on the binding of a fragment-based inhibitor of human uracil DNA glycosylase. Analysis of the free energies of binding in combination with co-crystal structures shows that the flexibility and strain of a given linker can have a significant impact on binding affinity even when the binding fragments are optimally positioned. Such effects are not apparent from inspection of structures and underscore the importance of linker optimization in fragment-based drug discovery efforts.
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影响因子：
12.7
作者：
Fleischmann, J;Kremmer, E;Niedobitek, G
通讯作者：
Niedobitek, G
影响因子：
2.1
作者：
Baltas, M;RaoufBenchekroun, K;Barthelat, JC
通讯作者：
Barthelat, JC
影响因子：
14.9
作者：
Krosky, Daniel J.;Bianchet, Mario A.;Seiple, Lauren;Chung, Suhman;Amzel, L. Mario;Stivers, James T.
通讯作者：
Stivers, James T.
影响因子：
20.3
作者：
Pasqualucci, L;Guglielmino, R;Polakiewicz, R
通讯作者：
Polakiewicz, R
影响因子：
3.5
作者：
Murray, CW;Verdonk, ML
通讯作者：
Verdonk, ML