Imaging and structural biology of molecular targets for psychotropic drugs

The research group has wide experience in using molecular graphics and other methods to study the molecular mechanisms of CNS active drugs. This application focuses on drugs acting on specific targets in brain, the serotonergic systems. The application wi ll enable further development and strengthen the molecular graphics and modelling research group in Tromsø. Major depression is a serious and incapacitating disorder with a heavy social burden and a substantial life time risk. Selective Serotonin Reuptake inhibitors (SSRIs) are currently the first line treatment of depression. Their antidepressant activity is believed to be exerted by blockade of the serotonine transporter protein (SERT), and thereby increased serotonergic neurotransmission. A major probl em with the SSRIs is their slow onset of anti-depressive action, mainly due to stimulation of pre-synaptic 5-HT1A autoreceptors. Agents combining inhibitorial effects on SERT with antagonistic activity at pre-synaptic 5-HT1A receptors are believed reduce the time to onset the action. The discovery and design of ligands combining inhibitorial effects on SERT and antagonistic effects on the 5-HT1A pre-synaptic receptors is the goal of the present proposal. Molecular modelling techniques will be used to cons truct 3D molecular images of the drug target proteins by homology with known protein structures. Automatic docking and affinity predictions of a test set of chemical compounds will be used to validate the molecular images. Chemical compounds that are synt hetically feasible will be screened against the homology models using the virtual screening module of the ICM program package. The most interesting compounds will be further studied by molecular dynamics methods for affinity predictions and the top ranked compounds will be passed on to our synthetic collaborators for synthesis and experimental assays.