NMR techniques for characterization of ligand binding: Utility for lead generation and optimization in drug discovery

Abstract

Over the last ten years, nmr spectroscopy has evolved into an important discipline in drug discovery. Initially, nmr was most useful as a technique to provide structural information regarding protein drug targets and target–ligand interactions. More recently, it has been shown that nmr may be used as an alternative method for identification of small molecule ligands that bind to protein drug targets. High throughput implementation of these experiments to screen small molecule libraries may lead to identification of potent and novel lead compounds. In this review, we will use examples from our own research to illustrate how nmr experiments to characterize ligand binding may be used to both screen for novel compounds during the process of lead generation, as well as provide structural information useful for lead optimization during the latter stages of a discovery program. © 1999 John Wiley & Sons, Inc. Biopoly 51: 221–243, 1999

Automated evaluation of chemical shift perturbation spectra: New approaches to quantitative analysis of receptor-ligand interaction NMR spectra

“…Finally, the use of peak shape information not only makes the peak mapping more robust to noise and signal overlap, but also provides an opportunity to generalize our program for evaluating other types of spectral changes. An example is the transferred NOE spectroscopy (Moore, 1999), where changes of peak intensities instead of peak locations are monitored. Common situations where the nearest peak-based approach may fail to find the correct matching between the reference peaks (in solid contours) and test peaks (in dotted contours).…”

Thermodynamics of binding interactions in the rational drug design process

“…Indirect methods that are available to measure K d values and, thus, van't Hoff enthalpies in this way include spectroscopic methods such as surface plasmon resonance [29][30][31] , NMR [32] and mass spectrometry [33] , chromatographic methods including frontal affinity chromatography [34] and capillary electrophoresis [35] , as well as standard methods, such as radioligand binding. A detailed description of each of these methods is beyond the scope of this review, but a generalisation of the method for determination of enthalpy by these indirect approaches is given briefly below.…”

Structural genomics for membrane proteins

“…2604 K. Lundstrom Structural genomics for membrane proteins NMR has been a complementary technology to X-ray crystallography [85]. Despite poorer resolution and molecular-weight limits, NMR has routinely been used in lead compound identification and evaluation [86]. Larger proteins have recently become feasible for NMR studies through developments in probe and software technologies.…”