title: What we have learned from crystal structures of proteins to receptor function.
abstract: The activity of ligand gated channels is crucial for proper brain function and dysfunction of a single receptor subtype have led to neurological impairments ranging from benign to major diseases such as epilepsy, startle diseases, etc. Molecular biology and crystallography allowed the characterization at the atomic scale of the first four transmembrane ligand gated channels and of proteins sharing a high degree of homology with the neurotransmitter-binding domain. Gaining an adequate knowledge of the structural features of the ligand binding pocket led to the possibilities of developing virtual screening based approaches and probing in silico the docking of very large numbers of molecules. Development of new computing tools further extended such possibilities and rendered possible the screening of the chemical universe database GDB-11, which contains all possible organic molecules up to 11 atoms of C, N, O and F. In the case of the nicotinic acetylcholine receptors molecules identified using such screening methods were synthesized and characterized in binding assays and their pose determined in crystal structure with the acetylcholine binding protein. However, in spite of these thorough approaches, functional studies revealed that these molecules had a greater affinity for the pore domain of the channel and acted as open channel blocker rather than binding site antagonist. In this work, we discuss the potential and current limitations of how progresses made with the crystal structures of ligand gated channels, or ligand binding proteins, can be used in combination with virtual screening and functional assays, to identify novel compounds.
authors.affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: J-L
authors.initials: JL
authors.lastname: Reymond
authors.forename: Ruud
authors.initials: R
authors.lastname: van Deursen
authors.forename: D
authors.initials: D
authors.lastname: Bertrand
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D005071:Evoked Potentials; D057166:High-Throughput Screening Assays; D006801:Humans; D058446:Ligand-Gated Ion Channels / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry*
chemical_list: D058446:Ligand-Gated Ion Channels; D008024:Ligands; D004364:Pharmaceutical Preparations; D011956:Receptors, Cell Surface