Enthalpy-Based Screening of Focused Combinatorial Libraries for the Identification of Potent and Selective Ligands
Enthalpy-Based Screening of Focused Combinatorial Libraries for the Identification of Potent and Selective Ligands
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DOI：
10.1021/acschembio.7b00717
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发表时间：
2017-12-01
影响因子：
4
通讯作者：
Pellecchia, Maurizio
中科院分区：
文献类型：
--
作者：
Baggio, Carlo;Udompholkul, Parima;Pellecchia, Maurizio
在现代药物发现中，生物物理方法（包括核磁共振光谱或表面等离子体共振）准确且明确地检测和表征配体蛋白质相互作用的能力使得这些方法相对于大量化合物的常规生化高通量筛选是优选的。然而，同时解决效力和选择性的配体筛选策略尚未完全开发。在这项工作中，我们提出了一种新的方法来筛选大集合的组合库：使用焓测量作为一个主要的筛选技术。我们证明，选择由焓（Δ H）驱动的粘合剂不仅是有效的，而且对给定的目标更具选择性的代理。这种通用和新颖的方法，我们称之为EPOS的Delta H筛选（聚焦位置扫描库的焓筛选），结合了聚焦组合化学的原理和快速量热测量：以有效地识别有效的和选择性的抑制剂。
In modern drug discovery, the,ability of biophysical methods, including nuclear magnetic resonance spectroscopy or surface plasmon resonance, to detect and characterize ligand protein interactions accurately and unambiguously makes these approaches preferred, versus conventional biochemical high throughput screening of large collections of compounds. Nonethe-less, ligand screening strategies that address simultaneously potency and selectivity have not yet been fully developed. In this work, we propose a novel method for screening large collections of combinatorial libraries :using enthalpy measurements as a primary screening technique. We demonstrate that selecting binders that are driven by enthalpy (Delta H) results in agents that are not only potent but also more selective for a given target. This general and novel approach, we termed Delta H Screening of EPOS (enthalpy screening of focused positional scanning library), combines the,principles of focused combinatorial chemistry with rapid calorimetry measurements:to efficiently identify potent and selective inhibitors.