Enthalpy-Based Screening of Focused Combinatorial Libraries for the Identification of Potent and Selective Ligands,ACS Chemical Biology

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Enthalpy-Based Screening of Focused Combinatorial Libraries for the Identification of Potent and Selective Ligands
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-11-02 00:00:00 , DOI: 10.1021/acschembio.7b00717
Carlo Baggio ₁ , Parima Udompholkul ₁ , Elisa Barile ₁ , Maurizio Pellecchia ₁

Affiliation

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.

中文翻译：

基于焓的聚焦组合库筛选，用于鉴定强效和选择性配体

在现代药物发现中，包括核磁共振波谱或表面等离振子共振在内的生物物理方法能够准确，明确地检测和表征配体-蛋白质相互作用的能力，使这些方法成为首选方法，而不是对大量化合物进行常规生物化学高通量筛选。然而，还没有完全开发出同时解决效价和选择性的配体筛选策略。在这项工作中，我们提出了一种新的方法，该方法使用焓测量值作为主要的筛选技术来筛选组合库的大集合。我们证明了选择由焓（ΔH）产生的药剂不仅对给定的目标有效，而且更具选择性。这是一般的和新颖的方法，我们称为Δ ħ的筛选˚F POS（焓筛选的聚焦位置扫描库），结合的原理专注组合化学快速热法测量，以有效地识别有效的和选择性的抑制剂。

更新日期：2017-11-02

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