SPR is a fast and straightforward method to estimate the binding constants of cyclic dinucleotides to their binding partners, such as STING or poxin

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hagen Sülzen, Martin Klima, Vojtech Duchoslav, Evzen Boura
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Abstract

The development of small molecule drugs that target protein binders is the central goal in medicinal chemistry. During the lead compound development process, hundreds or even thousands of compounds are synthesized, with the primary focus on their binding affinity to protein targets. Typically, IC50 or EC50 values are used to rank these compounds. While thermodynamic values, such as the dissociation constant (KD), would be more informative, they are experimentally less accessible. In this study, we compare isothermal calorimetry (ITC) with surface plasmon resonance (SPR) using human STING, a key protein of innate immunity, and several cyclic dinucleotides (CDNs) that serve as its ligands. We demonstrate that SPR, with recent technological advancements, provides KDs that are sufficiently accurate for drug development purposes. To illustrate the versatility of our approach, we also used SPR to estimate the KD of poxin binding to cyclic GMP-AMP (cGAMP) that serves as a second messenger in the innate immune system. In conclusion, SPR offers a high benefit-to-cost ratio, making it an effective tool in the drug design process.

Abstract Image

SPR是一种快速而直接的方法来估计环二核苷酸与其结合伙伴(如STING或毒素)的结合常数。
开发以蛋白质结合物为靶点的小分子药物是药物化学的中心目标。在先导化合物的开发过程中,数百甚至数千种化合物被合成,主要关注它们与蛋白质靶点的结合亲和力。通常,使用IC50或EC50值对这些化合物进行排序。虽然热力学值,如解离常数(KD),可以提供更多的信息,但它们在实验上很难获得。在这项研究中,我们比较了等温量热法(ITC)和表面等离子体共振(SPR),使用人STING(先天免疫的关键蛋白)和几种作为其配体的环二核苷酸(cdn)。我们证明,随着最近的技术进步,SPR为药物开发目的提供了足够准确的KDs。为了说明我们方法的多功能性,我们还使用SPR来估计毒素与环GMP-AMP (cGAMP)结合的KD, cGAMP是先天免疫系统中的第二信使。综上所述,SPR提供了很高的效益成本比,使其成为药物设计过程中的有效工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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