Biomolecular NMR: a chaperone to drug discovery

Abstract

Biomolecular NMR now contributes routinely to every step in the development of new chemical entities ahead of clinical trials. The versatility of NMR--from detection of ligand binding over a wide range of affinities and a wide range of drug targets with its wealth of molecular information, to metabolomic profiling, both ex vivo and in vivo--has paved the way for broadly distributed applications in academia and the pharmaceutical industry. Proteomics and initial target selection both benefit from NMR: screenings by NMR identify lead compounds capable of inhibiting protein-protein interactions, still one of the most difficult development tasks in drug discovery. NMR hardware improvements have given access to the microgram domain of phytochemistry, which should lead to the discovery of novel bioactive natural compounds. Steering medicinal chemists through the lead optimisation process by providing detailed information about protein-ligand interactions has led to impressive success in the development of novel drugs. The study of biofluid composition--metabonomics--provides information about pharmacokinetics and helps toxicological safety assessment in animal model systems. In vivo, magnetic resonance spectroscopy interrogates metabolite distributions in living cells and tissues with increasing precision, which significantly impacts the development of anticancer or neurological disorder therapeutics. An overview of different steps in recent drug discovery is presented to illuminate the links with the most recent advances in NMR methodology.

A novel method for protein‐ligand binding affinity prediction and the related descriptors exploration

“…As this affinity is mainly determined by the interaction between the ligand and the relevant receptor, the study of the relationship between the features of a ligand-protein complex and its binding affinity becomes very important in modern drug discovery. 1,2 Usually, binding affinity of a ligand to a given receptor can be determined by experimental ways, such as NMR spectrometry, [1][2][3] microcalorimetry, [4][5][6] and surface plasmon resonance, 7 but they are often time-consuming and expensive. Therefore, many in silico methods are developed to predict the binding affinity based on the properties of the ligand and the receptor.…”

NMR Screening and Hit Validation in Fragment Based Drug Discovery

“…A variety of biophysical methods have evolved for that task, including X-ray crystallography [24,25], surface plasmon resonance (SPR, [26]) and other labelfree biosensor technologies [27], mass spectrometry [28,29], fluorescence correlation spectroscopy [30], thermal shift analysis [31], and NMR spectroscopy (reviewed in a 2003 number of Current Topics in Medicinal Chemistry, volume 3, number 1; and elsewhere [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]). The use of biophysical methods to detect interactions does not rely on a particular biological assay, which may not be available because of lack of knowledge about the activity of the target or because the activity is simply too complex to develop a simple functional readout (for example, signaling proteins involved in transient protein-protein interactions).…”

NMR metabolomics and drug discovery

“…[25,26] The recent expansion into the analysis of the metabolome has also enabled NMR to contribute to the clinical validation step. [13,27,28] By far, this stage is the most challenging and expensive component of the drug discovery process, where a significant number of failures occur. [29,30] From the analysis of biofluids, tissues, and cell extracts, NMR can measure changes in the metabolome resulting from the biological activity of the drug lead.…”