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Thermodynamics of 'hydrophobic' versus 'hydrophilic' binding in ligand-protein complexes

配体-蛋白质复合物中“疏水”与“亲水”结合的热力学

基本信息

批准号：
BB/E000991/1
负责人：
Steve Homans
金额：
$ 41.14万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE000991%2F1
关键词：
Thermodynamics hydrophobic versus hydrophilic binding

项目摘要

Complex biological processes involve the binding of one molecule by another. In some cases this involves the binding of one protein by another, whereas in others the protein binds a small organic molecule ('ligand'). In certain instances, for example in a disease state, there is a need to discover a novel small molecule that binds more tightly (ie has higher affinity) than the natural ligand. Ideally, this novel molecule or 'lead', can be further developed as a drug molecule effective against the particular disease state. The binding process can be thought of as a 'shape' problem, whereby the strength of binding depends critically on shape complementarity between the ligand and the binding pocket on the protein. However, the binding process is more complicated than this, since it is also determined by the extent of dynamics ('floppiness') of the interacting partners. To complicate matters further, there is a third partner in the interaction, namely molecules of solvent water in which all biological interactions take place. The discovery of new drug molecules on the basis of structural information (structure-based drug design) is currently hampered by the lack of information on these additional component parts. For this reason many drugs are discovered by screening large numbers of discrete compounds, which can be very time-consuming. This proposal aims to quantify the contributions to binding affinity from the various components described above. Ultimately, this may enable us to predict binding affinities from protein structures using high-speed computers, thereby inproving the efficiency of the drug discovery process.

复杂的生物过程涉及一个分子与另一个分子的结合。在某些情况下，这涉及一种蛋白质与另一种蛋白质的结合，而在其他情况下，蛋白质结合小的有机分子（“配体”）。在某些情况下，例如在疾病状态下，需要发现比天然配体结合更紧密（即具有更高亲和力）的新型小分子。理想情况下，这种新型分子或“先导物”可以进一步开发为有效对抗特定疾病状态的药物分子。结合过程可以被认为是一个“形状”的问题，其中结合的强度主要取决于配体和蛋白质上的结合口袋之间的形状互补性。然而，结合过程比这更复杂，因为它还取决于相互作用伙伴的动态程度（“松弛”）。更复杂的是，在相互作用中还有第三个伙伴，即溶剂水分子，所有生物相互作用都发生在溶剂水分子中。基于结构信息的新药分子的发现（基于结构的药物设计）目前受到缺乏这些额外组成部分的信息的阻碍。因此，许多药物都是通过筛选大量离散化合物来发现的，这可能非常耗时。该提议旨在量化上述各种组分对结合亲和力的贡献。最终，这可能使我们能够使用高速计算机预测蛋白质结构的结合亲和力，从而提高药物发现过程的效率。