Guanine-rich sequences forming G-quadruplexes (GQs) are present in several genomes, ranging from viral to human. Given their peculiar localization, the induction of GQ formation or GQ stabilization with small molecules represents a strategy for interfering with crucial biological functions. Investigating the recognition event at the molecular level, with the aim of fully understanding the triggered pharmacological effects, is challenging. Native electrospray ionization mass spectrometry (ESI-MS) is being optimized to study these noncovalent assemblies. Quantitative parameters retrieved from ESI-MS studies, such as binding affinity, the equilibrium binding constant, and sequence selectivity, will be overviewed. Computational experiments supporting the ESI-MS investigation and boosting its efficiency in the search for GQ ligands will also be discussed with practical examples. The combination of ESI-MS and in silico techniques in a hybrid high-throughput-screening workflow represents a valuable tool for the medicinal chemist, providing data on the quantitative and structural aspects of ligand–GQ interactions.

中文翻译：

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结合电喷雾质谱 (ESI-MS) 和计算技术评估 G-四链体配体：优化命中发现的混合方法

形成 G-四链体 (GQ) 的富含鸟嘌呤的序列存在于从病毒到人类的多个基因组中。鉴于其独特的定位，用小分子诱导 GQ 形成或 GQ 稳定代表了一种干扰关键生物功能的策略。在分子水平上研究识别事件，以充分了解触发的药理作用，具有挑战性。天然电喷雾电离质谱 (ESI-MS) 正在优化以研究这些非共价组件。从 ESI-MS 研究中检索到的定量参数，如结合亲和力、平衡结合常数和序列选择性，将被概述。还将通过实际示例讨论支持 ESI-MS 研究并提高其在 GQ 配体搜索中的效率的计算实验。ESI-MS 和混合高通量筛选工作流程中的计算机技术代表了药物化学家的宝贵工具，可提供有关配体-GQ 相互作用的定量和结构方面的数据。