Comprehensive and High‐Throughput Exploration of Chemical Space Using Broadband ¹⁹F NMR‐Based Screening

Abstract

Fragment‐based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease‐relevant targets. Among the numerous screening techniques, fluorine‐detected NMR has gained popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library, and a sample composition optimized for a maximal number of compounds and minimal measurement time are required. Here, we introduce a comprehensive method that enabled the efficient assembly of a high‐quality and diverse library containing nearly 4000 fragments and screening for target‐specific binders within days. At the core of the approach is a novel broadband relaxation‐edited NMR experiment that covers the entire chemical shift range of drug‐like 19F motifs in a single measurement. Our approach facilitates the identification of diverse binders and the fast ligandability assessment of new targets.

Hydrogen Bond Acceptor Propensity of Different Fluorine Atom Types: An Analysis of Experimentally and Computationally Derived Parameters

“…Although less abundant, alkyl fluorinated motifs are now receiving increasing consideration. For example, they are now included in fluorinated fragment libraries for 19 F NMR screening [43,55–57] . These molecules have a higher degree of three‐dimensionality, often improved solubility in water [4,18,40] and the alkyl fluorine atom can participate in polar intramolecular and intermolecular interactions which have important implications for the chemical‐physical and structural properties of the molecules, [58–73] chemical reactions [13,38,74–79] and protein–ligand recognition [39,80] .…”

Application of Fragment-Based Drug Discovery to Versatile Targets

“…The wide dispersion of 19 F signals make it possible to use fragment mixtures in screening, which saves the data acquisition time. The availability of 19 F-labeled compound libraries makes 19 F-NMR more powerful in FBDD (Kang, 2019b;Lingel et al, 2020). 19 F-NMR is most attractive in fragment screening for the reason that a mixture of compounds can be screened and the correct hit can be readily picked out, making it become a high-throughput method.…”

Trendbericht: Kernmagnetische Resonanz

“…19 F-Screening-Methoden wurden auf RNA erweitert 30) und mit speziell entwickelten 1 ms langen Breitbandpulsen auf den gesamten aromatischen bis aliphatischen Bereich beschleunigt. 31) Noch breitere Bandbreiten sind durch verbesserte CHORUS-Pulse mit der Einschränkung längerer Pulslängen zu erreichen. 32) Um Mischungen und Metabolomics-Studien zu interpretieren, wurden ein Verfahren zum Assessment und die Anwendung von Real-time-Methoden eingeführt.…”