From genomics to drug targets

• Published in: Journal of psychopharmacology (Oxford) Vol. 20; no. 4 Suppl; p. 95
• Main Authors: Dahl, Svein G, Sylte, Ingebrigt
• Format: Journal Article
• Language: English
• Published: United States 01.07.2006
• Subjects: Animals; Binding Sites; Genomics - methods; Humans; Membrane Proteins - agonists; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - chemistry; Models, Biological; Models, Molecular; Protein Structure, Tertiary; Psychotropic Drugs - chemistry; Psychotropic Drugs - metabolism; Psychotropic Drugs - pharmacology; Receptors, Drug - agonists; Receptors, Drug - antagonists & inhibitors; Receptors, Drug - chemistry
• ISSN: 0269-8811
• DOI: 10.1177/1359786806066088

The era of molecular biology and cloning brought new knowledge about the structure and function of drug receptors, and demonstrated that the term 'receptor' must be distinguished from other molecular drug targets such as enzymes, transporters and ion channels. Analysis of the targets of all current therapeutic drugs has shown that more than 95% of these are proteins. The DNA sequencing of the entire human genome has led to identification of many previously unknown proteins that may represent potential drug targets. In order to understand fully the functional mechanisms of a protein, it is crucial to know its three-dimensional molecular structure. This may be determined experimentally by x-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy or electron microscopy, and computationally by structural bioinformatics and molecular modelling. The molecular targets of nearly all current psychotropic drugs are membrane proteins. These have proven extremely difficult to purify and crystallize due to their amphipathic surface, with a hydrophobic area in contact with membrane phospholipids and polar surface areas in contact with the aqueous phases on both sides of the membrane. We have used molecular modelling methods, based on crystal structures of related proteins, to model various neurotransmitter receptors and transporters. The receptor and transporter models have been used to study their structural properties, functional mechanisms and the molecular mechanisms of action of psychotropic drugs. Our results demonstrate the large structural flexibility of transporter and receptor proteins, with substantial movements and conformational changes taking place during substrate translocation in transporters, and by agonist induced receptor stimulation.