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A novel antidepressant therapy
Posted on February 21st, 2010 No commentsCurrent antidepressants usually marketed compensate the low level of serotonin, the main cause of depression, anxiety and mood problems. These compounds selectively block the re-uptake of neurotransmitter into the synaptic space. Serotonin still longer available for the interaction with its receptors located onto the plasma membrane of post synaptic neurons. Unfortunately, clinical studies reported an high variability in the response and some patients acquired resistance after few months of treatment. Furthermore, clinical efficacy has a lag of two or three weeks after starting the therapy, before obtaining significant benefit for patients.
Scientists for the Columbia University demonstrated that a possible responsible of the resistance is an auto-receptor for serotonin located onto the membrane of pre synaptic neurons that regulates serotonin release with negative feedback. Mouse carrying lower level of this receptor than normal mouse showed higher tolerance to environmental stress and other stimuli and a better response to traditional inhibitors. In human, high level of auto- receptor causes low reactivity of amygdale, a brain portion crucial to overcome stress and difficult situations. Inhibitors of this serotonin auto-receptor will be a novel drug useful to treat resistant forms of depression and anxiety or to improve activity of current antidepressant compounds. -
The importance of QSAR studies in pre-clinical phase of drug discovery
Posted on August 17th, 2009 No comments
QSAR is the acronym of quantitative structure activity relationship, is a modern tool to discover new molecules that could become drug. Indeed, a crucial step in the drug discovery process is the identification of lead compound, the first molecule that has an activity on the target and could be modified to improve its pharmaceutical features. Molecular modeling allows to show how this lead fits into the target, for instance a protein, and defines what are the important bonds that guarantee the interaction. The three-dimensional structure of the target is essential to perform this kind of studies and obtain results pretty sure.
It’s not a case that the major pharmaceutical companies have large structural and biochemical group in their Research & Development department. Anyway, an hypothetical model, based on structures of other protein similar to those of interest, can be build and tested: is the robustness of the model that determine the quality of the prediction. Indeed, in both cases virtual model can be used to screen libraries and identify the most promising compounds, named lead. Then, these molecules are tested in biochemical or biological assays to validate the activity. In this way, only few molecules of thousands that compose a library, can reach the bench and can be screened, by effectively reducing costs. Modifications of an active lead compound are crucial to improve its pharmaceutical properties and increase the likelihood to successfully enter in clinical phases. QSAR identifies all the positions that are important for the interaction between compound and target and suggests some chemical groups that could be inserted to further stabilize this binding. Thus, other compounds derive from this virtual study that have to be validated in experimental conditions. By analyzing the changes in the activities, it’s possible to define a quantitative relationship between structure modifications and activity itself.
Modifications that show an improvement in the activity are selected and further compounds are synthesized, by combining these changes. Again, a virtual screening is firstly run to check the new binding modalities and, then, experiments determine the activity. By repeating this process two or three times it’s possible to dispose on leads of second and third generation that have more chances to become drug. This pre-clinical phase could take some years, but efficiently reduces the cost of drug discovery. Indeed, the high rate of failure in the clinical phases, the most expensive part of the process, in part depends on the lack of accurate pre-clinical studies. QSAR is one of the tool now available to reduce the failure rate and identify only the compounds that could potentially have success. However, the results from clinical studies are always the limiting step to the entrance on the market of novel drugs. -
Challenging on drug combination
Posted on July 22nd, 2009 No commentsDrug combination represents an important field of research for a long series of reason. Firstly drug combination could have a therapeutic advantage if it generates synergy, so when the activity of two drug given in combination is higher than the sum of the activity of each drug given alone.
Unfortunately, synergy in the activity often determines synergy also in side effects. In literature it’s reported that synergistic combination could arise in more specific and particular cellular context than single agent activities. A simulation of bacterial metabolism allowed to perform multi-dose experiments relevant to several diseases and outlined the combinations that gave selective synergy in respect of drug target activity. For instance, an anti-inflammatory drug showed an increasing selectivity through different expression level of the target of another drug. The specificity of synergistic combinations generates new opportunities for therapeutic approach to improve the control of cellular system, so complex and interesting. Moreover, synergy could lead to decrease effective doses of the drug and, maybe, reduced collateral effects. Finally, formulation of couple of drugs in one pill could improve also the patient compliance. Much work has to be done to identify new combinations specially for drugs whose patent is terminated.
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