Baggio Carlo, Udompholkul Parima, Barile Elisa, Pellecchia Maurizio
Division of Biomedical Sciences, School of Medicine, University of California, Riverside , 900 University Avenue, Riverside, California 92521, United States.
ACS Chem Biol. 2017 Dec 15;12(12):2981-2989. doi: 10.1021/acschembio.7b00717. Epub 2017 Nov 2.
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. Nonetheless, 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 (ΔH) results in agents that are not only potent but also more selective for a given target. This general and novel approach, we termed ΔH screening of fPOS (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.
在现代药物研发中，包括核磁共振光谱法或表面等离子体共振在内的生物物理方法能够准确无误地检测和表征配体 - 蛋白质相互作用，这使得这些方法比传统的对大量化合物进行生化高通量筛选更受青睐。尽管如此，同时兼顾效力和选择性的配体筛选策略尚未得到充分发展。在这项工作中，我们提出了一种使用焓测量作为主要筛选技术来筛选大量组合文库的新方法。我们证明，选择由焓（ΔH）驱动的结合剂会产生不仅效力强而且对给定靶点更具选择性的药物。这种通用且新颖的方法，我们称之为聚焦位置扫描文库的ΔH筛选（fPOS的焓筛选），它将聚焦组合化学原理与快速量热法测量相结合，以有效识别强效和选择性抑制剂。
