Drug Discovery and Development: the Role of NMR

Abstract

NMR spectroscopy has been a technology of fundamental importance to drug discovery and development for the past 40-50 years, principally through its use in the structure elucidation of leads, drugs, their synthetic intermediates, and the degradation products and impurities of those drug molecules. In the past 30 years, another major area of application of NMR spectroscopy has been metabolic profiling or metabonomics studies of drug metabolism, drug safety, drug efficacy, and disease, through studies of biological fluids such as urine and plasma, representing a change in application from the chemical to the biological sciences. This trend has continued with significant progress in the application of in vivo MRI and magnetic resonance spectroscopy (MRS) to the study of disease states and their treatment in patients and in animal models. More recently, new applications of NMR spectroscopy have emerged such as hit-finding and hit-to-lead optimization, impacting directly on these early stages of the drug discovery process. Finally, the discovery of completely new areas, led by NMR spectroscopy, such as pharmacometabonomics, holds out the promise of improvements in personalized medicine in the future. This article will briefly cover all of these areas, and more, as a prelude to more detailed treatments in the following articles of this work.

Comparison of19F NMR and14C Measurements for the Assessment of ADME of BYL719 (Alpelisib) in Humans

“…NMR is/has been used for a number of applications in biomedical research and development, including metabolomics, in vivo magnetic resonance spectroscopy, and pharmaceutical analysis [drug identification, drug impurity characterization, degradation studies, drug isomeric composition, and analysis of counterfeits (Holzgrabe, 2010;Malet-Martino and Holzgrabe, 2011;Everett, 2015)]. Quantitative NMR has also been used for drug metabolism investigations, such as quantification of biologically isolated metabolites for use in pharmacological activity testing (Mutlib et al, 2011), as standards for quantitative assays to address MIST guidance concerns (Espina et al, 2009;Walker et al, 2011) or in preclinical in vivo efficacy models (Walker et al, 2014).…”

NMR-Based Metabolomics in Metal-Based Drug Research

“…This was last used to describe the quantitative measure of the metabolic, multi-parametric, and time-correlated response that a living system gives to a (patho) physiological stimuli or to genetic modifications [5]. Instead, the later definition of “metabolomics” consists of the identification and quantification of all the main low-molecular-weight metabolites/intermediates that vary according to the physiological or pathological state of the cell, tissue, organ, or organism of a biological system [6,7,8,9]. However, although some confusion has crept into the field, the difference in the use of metabolomics and metabonomics over the recent years has been clearly described [10], and nowadays the two terms are often used interchangeably [11].…”

“…Traditional methods require separation and optimization of the separation condition each time, followed by identification. Often, multiple slow separations (up to 72 h per sample) are necessary, and intensive manual work is needed, in addition to constant supervision and high-level skills [7,10]. In this context, the use of NMR spectroscopy in metabolomics studies has been given high throughput, thanks to the potential of this specific technique.…”

“…Due to the recent strong improvements of NMR technique and technologies, the NMR-based metabolomic is becoming a fast-growing and powerful technology [7]. Such improvements are essentially related to more reliable spectrometers, especially highly-sensitive NMR probes, with versatile acquisition sequences that can allow faster performance and substantial NMR experiments.…”

Molecular Dynamics of Bioinspired Nanotubes

“…a drug binding to its target. Experimental techniques, such as Nuclear Magnetic Resonance [114,115,116] or Isothermal Titration Calorimetry [117,118], can be used to calculate binding energies between macromolecules, but are limited by the nature and the size of the molecules. Additionally, experimental techniques measure an ensemble average without detailed knowledge for the contributions of the conformations averaged over.…”