BACKGROUND AND PLATFORM DESCRIPTION
The mood disorders, which refer to all types of depression and bipolar disorders, are among the most common diseases affecting the population of people aged 18 to 44 years, constituting the leading causes of disability and premature death. According to WHO, depression affects more than 120 million people worldwide and has lifetime prevalence in the range of 10 % to 15 %. The most commonly prescribed antidepressant drugs act by targeting the serotonin and/or noradrenaline transporters (SERT and NET, respectively). However, the current drugs are characterised by numerous adverse side effects, a delayed onset of action and lack effect in a significant proportion of patients, and the need for new antidepressant drugs is hence high.
We have recently developed a complex research program in which discovery of new potential drug candidates was organized as a multi-level research system within an academia-based platform (cns-patform.eu). As an extension of the platform, the current projects aims at further developing the Platform research, using the results obtained in the previous project and extending its scope on non-aminergic targets for antidepressant drug action. In the current project, we aim to identify new compounds targeting the serotonin transporter and the metabotropic glutamate 7 (mGlu7) and GABAB receptors, and to identify hybrid SERT-5-HT receptor compounds.
The Platform functions on four complementary modules, combining in silico, in vitro and in vivo drug discovery approaches. In the molecular modeling module, tools and methods are developed and used for multistep virtual screening of large compound databases. Our virtual screening protocols combine ligand- and structure-based VS approaches, such as homology modelling of the targets of interest, pharmacophore modelling and filtering. Ligand design for rational synthesis of mGlu7 and hybrid SERT-5-HT ligands in the second module is also performed. In the third module, biochemical characterization of compounds acquired using virtual screening or synthesis is performed, while in the fourth module, pharmacological characterization of selected compounds by testing antidepressant activity in in vivo assays is undertaken.
The platform is a collaboration (link to partners) between the Institute of Pharmacology, Polish Academy of Sciences (leading partner), Kraków, Poland, the University of Tromsø, The Arctic University of Norway, Tromsø, Norway, and the National Medicines Institute, Warsaw, Poland.