title: Beyond Membrane Protein Structure: Drug Discovery, Dynamics and Difficulties.
abstract: Most of the previous content of this book has focused on obtaining the structures of membrane proteins. In this chapter we explore how those structures can be further used in two key ways. The first is their use in structure based drug design (SBDD) and the second is how they can be used to extend our understanding of their functional activity via the use of molecular dynamics. Both aspects now heavily rely on computations. This area is vast, and alas, too large to consider in depth in a single book chapter. Thus where appropriate we have referred the reader to recent reviews for deeper assessment of the field. We discuss progress via the use of examples from two main drug target areas; G-protein coupled receptors (GPCRs) and ion channels. We end with a discussion of some of the main challenges in the area.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK. philip.biggin@bioch.ox.ac.uk.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Biggin
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Aldeghi
authors.affiliation: Evotec Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bodkin
authors.affiliation: Evotec Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
mesh_terms: D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D005544:Forecasting; D054828:Histamine H3 Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000188:drug therapy; D064446:Orexin Receptors / Q000187:drug effects; D011485:Protein Binding; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: C578626:HCRTR2 protein, human; C418607:HRH4 protein, human; D054828:Histamine H3 Antagonists; C103263:MCHR1 protein, human; D008565:Membrane Proteins; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D017481:Receptors, Somatostatin; D058826:Serotonin 5-HT2 Receptor Agonists; D014867:Water
keywords: Docking; G-protein coupled receptor; Glutamate receptor; Ion channels; Molecular dynamics; Simulation; Structure based drug design; Virtual screening