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

INPHARMA：一种基于 NMR 的高效药物结构设计方法

• 批准号: 193361429
• 负责人: Professorin Dr. Teresa Carlomagno
• 金额: --
• 依托单位: School of Biosciences
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/193361429?language=en
• 关键词: INPHARMA; efficient; NMR; based; methodology

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.

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。

项目成果

The description of protein internal motions aids selection of ligand binding poses by the INPHARMA method

蛋白质内部运动的描述有助于通过 INPHARMA 方法选择配体结合姿势

• DOI: 10.1007/s10858-012-9662-1
• 发表时间: 2012
• 期刊: Journal of Biomolecular NMR
• 影响因子: 2.7
• 作者: B. Stauch;J. Orts;T. Carlomagno
• 通讯作者: T. Carlomagno

An NMR-based scoring function improves the accuracy of binding pose predictions by docking by two orders of magnitude

基于 NMR 的评分函数通过对接将结合姿势预测的准确性提高了两个数量级

• DOI: 10.1007/s10858-011-9590-5
• 发表时间: 2012
• 期刊: Journal of Biomolecular NMR
• 影响因子: 2.7
• 作者: J. Orts;S. Bartoschek;C. Griesinger;P. Monecke;T. Carlomagno
• 通讯作者: T. Carlomagno

Accounting for conformational variability in protein-ligand docking with NMR-guided rescoring.

通过 NMR 引导的重新评分来解释蛋白质-配体对接中的构象变异

• DOI: 10.1021/ja4007468
• 发表时间: 2013
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: L. Skjærven;L. Codutti;A. Angelini;M. Grimaldi;D. Latek;P. Monecke;M. Dreyer;T. Carlomagno
• 通讯作者: T. Carlomagno

Identification of new hit scaffolds by INPHARMA-guided virtual screening

通过 INPHARMA 引导的虚拟筛选鉴定新的命中支架

• DOI: 10.1039/c5md00116a
• 发表时间: 2015
• 期刊: MedChemComm
• 作者: J. Sikorska;L. Codutti;L. Skjærven;B. Elshorst;R. Saez-Ameneiro;A. Angelini;P. Monecke;T. Carlomagno
• 通讯作者: T. Carlomagno