Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1α protein-protein interface.
Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1α protein-protein interface.
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DOI：
10.1016/j.chembiol.2012.08.015
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发表时间：
2012-10-26
影响因子：
--
通讯作者：
Ciulli A
中科院分区：
文献类型：
--
作者：
Van Molle I;Thomann A;Buckley DL;So EC;Lang S;Crews CM;Ciulli A
片段筛选被广泛用于确定药物设计的有吸引力的起点。然而，它的潜力和局限性，以评估往往具有挑战性的蛋白质：蛋白质界面的易处理性一直未充分探索。在这里，我们解决这个问题，通过系统的解构pVHL：HIF-1α相互作用的铅样抑制剂成其组成片段。使用通常用于筛选的生物物理技术，我们只能检测到违反三法则的片段的结合，这些片段比通常针对经典可药用靶标筛选的片段更复杂，并且在界面处占据两个相邻的结合亚位点而不是一个。基于锚定片段的配体和基团亲脂性效率的分析被应用于解剖各个亚位点和结合热点的探针。我们的研究结果的影响，以片段为基础的方法靶向蛋白质接口进行了讨论。
Fragment screening is widely used to identify attractive starting points for drug design. However, its potential and limitations to assess the tractability of often challenging protein:protein interfaces have been underexplored. Here, we address this question by means of a systematic deconstruction of lead-like inhibitors of the pVHL:HIF-1α interaction into their component fragments. Using biophysical techniques commonly employed for screening, we could only detect binding of fragments that violate the Rule of Three, are more complex than those typically screened against classical druggable targets, and occupy two adjacent binding subsites at the interface rather than just one. Analyses based on ligand and group lipophilicity efficiency of anchored fragments were applied to dissect the individual subsites and probe for binding hot spots. The implications of our findings for targeting protein interfaces by fragment-based approaches are discussed.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.7
作者：
Dalvit, C;Fogliatto, G;Stockman, B
通讯作者：
Stockman, B
影响因子：
64.8
作者：
Hon, WC;Wilson, MI;Jones, EY
通讯作者：
Jones, EY
影响因子：
120.1
作者：
Leeson, Paul D.;Springthorpe, Brian
通讯作者：
Springthorpe, Brian