This chapter looks at what happens from the moment that a pharmaceutical company or university research group initiates a new medicinal chemistry project through to the identification of a lead compound. It focuses on pharmaceutical companies which tend to concentrate on developing drugs for diseases prevalent in developed countries. These comapnies also aim to produce compounds with better properties than existing drugs. It also shows how a molecular target influences a particular disease when affected by a drug. The chapter discusses compounds that can be tested by nuclear magnetic resonance (NMR) spectroscopy as a result of their affinity to a macromolecular target. It defines a lead compound as a structure that shows a useful pharmacological activity and can act as the starting point for drug design.
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Chapter
Drug discovery: finding a lead
Chapter
Nuclear magnetic resonance
This chapter gives an account of the principles that govern spectroscopic transitions
between spin states of nuclei in molecules. It describes simple experimental arrangements
for the detection of these transitions in nuclear magnetic resonance (NMR) spectroscopy. It
shows how NMR spectroscopy is used widely in chemistry and medicine. It also discusses
resonant absorption which occurs when the separation of the energy levels of spins in a
magnetic field matches the energy of incident photons. The chapter highlights the
application of resonance which depends on the fact that many nuclei possess spin angular
momentum. It highlights nuclear spin quantum number, I, of a nucleus is
either a non-negative integer or half-integer.
Chapter
Protein structure determination
This chapter discusses protein structure determinations, which involve experimental and computational methods, and combined applications of both. For many years, X-ray crystallography and fibre diffraction were the only methods for determining the positions of individual atoms in macromolecular structures. A companion appeared in the 1980s, when K. Wüthrich, R.R. Ernst, and their coworkers developed methods for solving protein structures by nuclear magnetic resonance (NMR) spectroscopy. With a third technique, cryo-electron microscopy (cryo-EM), it has been possible to determine structures of large aggregates, including viral capsids, large protein complexes, and intact ribosomes. Cryo-EM of large multiprotein complexes plus X-ray crystal structures of individual components has proved a powerful combination. The chapter also considers protein structure prediction and modelling.
Chapter
NMR experiments
P.J Hore
This chapter explains how nuclear magnetic resonance (NMR) experiments work. Modern NMR spectroscopy is much more than simply recording a spectrum and interpreting the positions, widths, and intensities of the lines. The spins can be manipulated to tailor the information that appears in the spectrum. The chapter begins by introducing the 'vector model'. Although it has its origin in the quantum mechanics of spin angular momentum, it has the distinct advantage of being pictorial and essentially non-mathematical. The disadvantage is that it only helps us to understand the simplest NMR experiments. The chapter then uses the vector model to discuss two techniques for measuring spin relaxation times and an important method for sensitivity enhancement (Insensitive Nuclei Enhanced by Polarization Transfer or INEPT).
Chapter
Rotational and vibrational spectroscopy
This chapter presents a brief introduction to rotational and vibrational spectroscopy. It explains how pure rotational spectroscopy can be used in the precise determination of molecular geometry in small molecules and provide a direct means to deduce the shape of larger molecules. It also looks at how vibrational spectroscopy can be used in the measurement of geometrical parameters of gas phase molecules and in providing information about the structure and shape of molecules in the condensed phase. The chapter discusses the important role vibrational spectroscopy plays in characterization and analysis in organic chemistry where it is used typically in tandem with mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. It analyses concepts on a molecular scale by exploring how light interacts with the energy levels associated with rotational and vibrational degrees of freedom.
Chapter
Nuclear magnetic resonance spectroscopy
This chapter talks about the concept of nuclear spin, which focuses on nuclear magnetic moments and their study through nuclear magnetic resonance (NMR) spectroscopy. It uses the proton,1H, as the simplest example that illustrates how the phenomenon arises and describes the operation of a basic NMR spectrometer. It also describes a range of organic molecules that show how electronic effects of different substituent groups enable these to be recognized by the chemical shifts of the protons concerned, leading to the use of the technique as a diagnostic tool. The chapter analyses the occurrence of spin–spin splittings that demonstrate how neighbouring protons interact with each other. It discusses the development of Fourier transform instrumentation and its application to NMR spectroscopy and outlines the principles and uses of magnetic resonance imaging (MRI) in medically-related studies.
Chapter
Nuclear magnetic resonance (NMR) spectroscopy
This chapter evaluates nuclear magnetic resonance (NMR) spectroscopy. NMR is the most powerful and widely used spectroscopic method for the investigation of the molecular structures of compounds. It yields information about the shape and symmetry of molecules. For many common atom types, NMR spectroscopy defines the different environments present and their numbers. Analysis of NMR spectra often allows the full molecular configuration of a molecule to be determined. The technique also provides useful information about the rate and nature of ligand interchange in fluxional molecules and can be used to follow reactions and so determine their mechanistic pathway. While diffraction techniques usually produce accurate interatomic distances and angles, NMR studies generally yield more limited information on the separation of nuclei, such as which atoms are bonded or close neighbours in a molecule. The chapter then looks at insensitive nucleus enhancement by polarization transfer (INEPT) and COSY (Correlated Spectroscopy) NMR spectrum.
Chapter
The solid state
This chapter studies the solid state. Although NMR spectroscopy in solution continues to be the most widely used magnetic resonance spectroscopic technique, NMR in the solid state is rapidly growing in importance. In addition to the problems of low sensitivity and low natural abundance for many important nuclides encountered in solution, NMR in the solid state faces additional challenges due to interactions such as dipolar coupling, chemical shift anisotropy, and quadrupolar interactions that are averaged out in solution by molecular tumbling but remain in the solid state due to the restricted mobility of the molecules/ions. Cross-polarization can be used to improve the signal to noise in spectra by allowing more scans to be acquired for signal averaging in the same amount of time. Analysis of CP build-up rates also provides information about things such as internuclear distances and molecular motions.
Chapter
Pulse techniques in NMR
This chapter covers pulse techniques in nuclear magnetic resonance (NMR). Sequences
of pulses of radiofrequency radiation manipulate nuclear spins, leading to the
efficient acquisition of NMR spectra and the measurement of relaxation times.
Relaxation primarily refers to the process by which the magnetization returns to its
equilibrium value. The chapter elaborates on the nuclear Overhauser effect, which
makes use of the relaxation caused by the dipole-dipole interaction of nuclear
spins, referencing the modification of the intensity of one resonance by the
saturation of another. It also mentions how the modern implementation of NMR
spectroscopy triggers many possibilities for the development of more sophisticated
experiments.
Chapter
Spectroscopy
This chapter discusses mass spectrometry, infrared (IR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. The basic function of a mass spectrometer is to measure the mass of a molecule or, more correctly, an ion. A mass spectrometer can only separate and detect charged ions; neutral molecules cannot be detected. Both positive and negative ions can be detected, depending on the technique used. In IR spectroscopy, IR radiation is shone through a sample and certain frequencies (energies) are absorbed as molecules move to higher vibrational energy levels. Meanwhile, NMR looks at the environments of nuclei within molecules and is able to detect which nuclei are close to one another on the bonding network.
Chapter
Resonance spectroscopy
This chapter examines resonance spectroscopy. Nuclear magnetic resonance (NMR) spectroscopy is probably the single most widely used and important physical technique available to the modern practical chemist. This is because of its wide applicability, its relative ease of use, and the amount of chemical and structural information that can be obtained from its use. The technique is frequently associated only with proton and carbon nuclei but there are many other elements to which it can potentially be applied. The chapter then looks at nuclear quadrupole resonance (NQR) spectroscopy. In NMR experiments, an external field is applied to cause a splitting of the normally degenerate nuclear spin states, but this is not necessary in NQR experiments because when there is an asymmetric charge distribution within the molecule, a molecular electric field gradient is generated. The chapter also considers electron spin resonance (ESR) spectroscopy.
Chapter
Putting it all together
This chapter presents some worked problems where a number of spectroscopic techniques are brought to bear on the same problem. It is rarely sensible, and frequently not possible, to rely on a single spectroscopic method to provide an unambiguous answer to the identity of an unknown product. Usually, the more techniques that are used, the more confident one can be in assigning the identity of a compound and its potential structure. One problem concerns the identification of a gaseous product which results from the reaction of (Me2HSi)2S with methanol. The presence of a variety of protons makes nuclear magnetic resonance (NMR) spectroscopy a likely candidate, provided one can find a solvent in which this gas is soluble. For a solid sample, it is possible to try and obtain the molecular composition by elemental analysis. For a volatile sample, mass spectrometry is more straightforward.
Chapter
Nuclear magnetic resonance spectroscopy: the basics
This chapter describes nuclear magnetic resonance (NMR) spectroscopy as the most powerful and versatile of all analytical techniques used by organic chemists. It highlights the spectroscopic features of NMR spectroscopy, which correlate with individual atoms within a molecule rather than groups of atoms. It also emphasizes the possibility of determining the structures of small-to-medium-sized organic molecules in solution and focuses on solution spectroscopy as it is in this form of NMR that is the most useful in organic chemistry. The chapter explains that NMR occurs as a result of the fact that the nuclei of certain atoms possess spin, which is characterized by a quantum number and takes integer and half-integer values. It points out that nuclei with zero spin are not amenable to NMR observation, although most elements have at least one isotope that possess nuclear spin.
Chapter
Introduction
P.J Hore
This introductory chapter provides an overview of nuclear magnetic resonance (NMR). Molecules are inconveniently small and difficult to observe directly. To learn about their structures, motions, reactions, and interactions we need microscopic spies able to relay information on their molecular hosts without significantly perturbing them. The spies that form the subject of this book are atomic nuclei, and the attribute that makes them successful at espionage is their magnetism. The chapter then looks at spin angular momentum and nuclear magnetism. In a magnetic field, the energy levels are split apart by an amount proportional to the size of the nuclear magnetic moment and the strength of the field. NMR spectroscopy uses electromagnetic radiation to cause transitions between the energy levels.
Chapter
Fundamental aspects of characterisation methods in inorganic chemistry
This chapter discusses the fundamental aspects of characterization methods in inorganic chemistry. While not all of the techniques described in this book use the electromagnetic spectrum as a probe of the structures of inorganic molecules and materials, four of the main physical methods — NMR spectroscopy, vibrational spectroscopy, X-ray diffraction, and ultraviolet-visible (UV-vis) spectroscopy — all employ light of a specific range of wavelengths. Other less commonly employed techniques, such as Mössbauer spectroscopy, X-ray absorption spectroscopy (XAS), electron paramagnetic resonance (EPR), and nuclear quadrupole resonance (NQR) spectroscopy, also use portions of the electromagnetic spectrum covering the energy range from gamma rays, with wavelengths of a few picometres, to microwaves, with wavelengths of centimetres to metres. Because the full electromagnetic spectrum is employed to characterize inorganic compounds, the data obtained covers a very large wavelength and, therefore, energy range. The chapter then describes energy unit conversions and Fourier transforms in spectroscopy.
Chapter
Chemical analysis: characterizing chemical compounds
This chapter explores chemical analysis—the process of characterizing chemical compounds. It begins by looking at separation techniques, including solvent extraction, chromatography, electrophoresis, and centrifugation. The chapter then considers the use of mass spectrometry in determining the mass of a compound in a sample. It also outlines different spectroscopic techniques, which use the behaviour of compounds when they interact with electromagnetic radiation to help characterize them. Different spectroscopic techniques use different parts of the electromagnetic spectrum to ask different questions about chemical structure. These spectroscopic techniques include nuclear magnetic resonance (NMR) spectroscopy, infrared spectroscopy, and UV–visible spectroscopy. Finally, the chapter discusses X-ray crystallography, which reveals the three-dimensional structure of a compound in crystalline form.
Chapter
Fundamentals
This chapter provides an overview of nuclear magnetic resonance (NMR) spectroscopy, which is commonly first encountered in organic chemistry, and attention is focused on the NMR spectroscopy of a single element, hydrogen. There are, however, many other elements that have isotopes with nuclear spin; if these elements are taken into account, NMR becomes perhaps the most important spectroscopic technique today for the characterization of inorganic compounds in solution and is of growing importance in the solid state. In solution, spin ½ nuclei give well-resolved, sharp resonances for each NMR active site in the molecule, while in the solid state, cross-polarization results in an increase in sensitivity and magic angle spinning results in an increase in resolution. The rules for interpreting NMR spectra depend only on the nuclear spins present. The chapter then presents some basic theory of NMR and a formalism for the prediction of NMR spectra in solution.
Book
Jonathan A. Iggo and Konstantin V. Luzyanin
NMR Spectroscopy in Inorganic Chemistry offers a non-mathematical grounding in the physics of NMR spectroscopy and explores why the spectra look the way they do, providing a useful collection of NMR examples and trends in NMR parameters from inorganic chemistry. The first chapter covers the fundamentals. The second chapter looks at structure determination. The third chapter covers dynamic processes and NMR. The last chapter is about the solid state.
Chapter
Taking it further
This chapter explores new developments in organic chemistry. There is a need for theories, but all good theories are firmly based on facts. ‘How do you know that?’ and ‘How do you show that this statement is true?’ are questions we will be asking more often in the future. It is in answering these questions that the armoury of techniques of the modern organic chemist comes into play, from chemical kinetics to nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography. The chapter then looks at mechanisms and molecular orbitals, before considering functional group chemistry. It also highlights some current research projects in organic chemistry, including the biosynthesis of ethane; the synthesis of new anti-cancer agents; and fluorescent indicators for calcium ions.
Chapter
Instrumental Analysis
This chapter expounds on the types of instrumental analysis used in chemical laboratories, especially those working with organic compounds. It also notes the fragmentation patterns that characterize a molecule. Mass spectrometry is utilized to search for a compound's molecular formula, while infrared spectroscopy involves the absorption of radiation in the electromagnetic spectrum's infrared region. The energy absorbed makes the bonds vibrate more energetically. Nuclear magnetic resonance (NMR) spectroscopy calculates nuclei's protons and neutrons that possess nuclear spins. The chapter also explains the process of spin-spin splitting or coupling in the NMR spectra as it depends on the number of adjacent protons.
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