Ligand-Based Fluorine NMR Screening: Principles and Applications in Drug Discovery Projects

Abstract

Ligand-based fluorine NMR screening has gained popularity in drug discovery projects during the past decade and has become a powerful methodology to produce high quality hits. Its high sensitivity to protein binding makes it particularly suitable for fragment screening, allowing detection and binding strength measurement of very weak affinity ligands. The screening can be performed in direct or competition format, and its versatility allows application to complex biological and chemical systems. As the potential of the methodology has now been recognized and successfully demonstrated in several relevant medicinal chemistry projects, it is now an appropriate time to report the learned lessons and point the way to the future. In this Perspective the principles of the methodology along with several applications to pharmaceutical projects are presented.

Nuclear-spin-pattern control of electron-spin dynamics in a series of V(iv) complexes

“…A system patterned with 19 F nuclei is in contrast particularly advantageous since 19 F NMR is readily performed. [78][79][80] It is in these directions that we are now working.…”

Library Design Strategies To Accelerate Fragment‐Based Drug Discovery

“…30 fragments. [23,25] 19 FNMR spectroscopy screening typically relies on transverse (T 2 )r elaxation-based experiments.T hese exploit the large differencei nt umbling rates between large biomolecules and fragments, along with ac hemical exchange contribution that arises from the difference in chemical shifts between free and bound states ( Figure 1). The following sectionh ighlights a few examples of fluorinated fragment libraries used for 19 FNMR spectroscopy screening.…”

1H-NMR Determination of Organic Compounds in Municipal Wastewaters and the Receiving Surface Waters in Eastern Cape Province of South Africa

“…NMR is also a powerful tool for determining the chemical properties of functional groups in bio-macromolecules, such as the ionization states of some groups at enzymes active sites [14]. It provides a unique molecular movement and interaction profiles with information on protein functions, which are necessary for drug development [15]. NMR spectroscopy is a useful tool in drug screening, identification and determination of metabolites interactions with enzymes, receptors and other proteins [16].…”

“…NMR spectroscopy is a useful tool in drug screening, identification and determination of metabolites interactions with enzymes, receptors and other proteins [16]. The high sensitivity of NMR to protein binding has made it possible for the screening of ligands bindings [15,17].…”