title: Biophysical methods in drug discovery from small molecule to pharmaceutical.
abstract: Biophysical methods have become established in many areas of drug discovery. Application of these methods was once restricted to a relatively small number of scientists using specialized, low throughput technologies and methods. Now, automated high-throughput instruments are to be found in a growing number of laboratories. Many biophysical methods are capable of measuring the equilibrium binding constants between pairs of molecules crucial for molecular recognition processes, encompassing protein-protein, protein-small molecule, and protein-nucleic acid interactions, and several can be used to measure the kinetic or thermodynamic components controlling these biological processes. For a full characterization of a binding process, determinations of stoichiometry, binding mode, and any conformational changes associated with such interactions are also required. The suite of biophysical methods that are now available represents a powerful toolbox of techniques which can effectively deliver this full characterization.The aim of this chapter is to provide the reader with an overview of the drug discovery process and how biophysical methods, such as surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), nuclear magnetic resonance, mass spectrometry (MS), and thermal unfolding methods can answer specific questions in order to influence project progression and outcomes. The selection of these examples is based upon the experiences of the authors at AstraZeneca, and relevant approaches are highlighted where they have utility in a particular drug discovery scenario.
authors.affiliation: AstraZeneca R&D, Macclesfield, UK.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Holdgate
authors.forename: Stefan
authors.initials: S
authors.lastname: Geschwindner
authors.forename: Alex
authors.initials: A
authors.lastname: Breeze
authors.forename: Gareth
authors.initials: G
authors.lastname: Davies
authors.forename: Nicola
authors.initials: N
authors.lastname: Colclough
authors.forename: David
authors.initials: D
authors.lastname: Temesi
authors.forename: Lara
authors.initials: L
authors.lastname: Ward
mesh_terms: D001665:Binding Sites; D002151:Calorimetry; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009696:Nucleic Acids / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*; D013237:Stereoisomerism; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D009696:Nucleic Acids; D011506:Proteins; D054852:Small Molecule Libraries