INPHARMA: an efficient NMR-based methodology for structure-based drug design

小分子在蛋白质、核酸和分子机器的功能调节中起着基础性作用。选择性地改变仅一种或几种细胞靶标的功能的特异性结合剂的开发依赖于靶标活性位点的结构信息的可用性及其与低亲和力配体的相互作用模式，例如在筛选实验中鉴定。最近，我们已经开发了一种新的NMR方法，INPHARMA，它提供了一个共同的目标低亲和力配体的相对结合模式。根据基于结构的药物设计工作流程，INPHARMA工作流程目前包括从计算机生成的对接姿势库中选择结合模式，因此需要脱辅基受体的结构。在本提案中，我们计划使INPHARMA适用于结构未知的蛋白质靶点。我们将开发一种方法，允许直接访问的受体/配体复合物的结合位点的结构，结合口袋的形状和配体结合模式被定义的INPHARMA数据。这可能会通过释放对受体结构数据的需求来改变SBDD的方式。

Small molecules play a fundamental role in the regulation of the function of proteins, nucleic acids and molecular machines. The development of specific binders that selectively alter the function of only one or a few cellular targets relies on the availability of structural information for the target active site and its mode of interaction with low affinity ligands, identified for example in screening experiments. Recently we have developed a new NMR methodology, INPHARMA, which provides access to the relative binding mode of low-affinity ligands to a common target. In accordance with structure-based drug design workflows, the INPHARMA workflow currently includes selection of binding modes from a pool of computer-generated docking poses and therefore requires a structure of the apo-receptor. In this proposal we plan to make INPHARMA applicable to protein targets without a known structure. We will develop an approach that allows direct access to the structure of the receptor/ligand complex at the binding site, with both the shape of the binding pocket and the ligand binding-mode being defined by the INPHARMA data. This will possibly transform the way SBDD is conducted by releasing the need for structural data on the receptor.