A Bulgarian multidisciplinary team has combined computational modelling approaches to predict the pharmacokinetic and pharmacodynamic profiles of small molecules
Recently, metabolic syndrome, which includes hypertension, type 2 diabetes and obesity, has reached epidemic proportions, leading to an increased risk of developing cardiovascular diseases. The nuclear peroxisome proliferator-activated receptor gamma (PPARγ) is a protein that regulates glucose and lipid homeostasis and is an important pharmacological target for the treatment of type 2 diabetes and other metabolic disorders.
The trend in the development of PPARγ modulators has been shifted from design of full agonists (maximal activation) towards the identification of partial agonists (partial activation) in order to reduce the undesirable effects. In general, identification and development of active molecules for disease prevention or treatment is labor-, time- and cost-consuming process.
In silico studies have increased the efficiency of the process of identifying potentially active molecules a lot, leading to a significant acceleration and notable reduction in the cost involved, as well as to avoiding unnecessary animal testing in assessing toxic effects. The combination of diverse in silico approaches to assess the metabolites of a molecule and their capacity to modulate by weak partial agonism the activity of PPARγ distinguishes this research from previous studies that rarely focus on predicting the mechanism of action of metabolites and on the discrimination of individual sub-classes of partial agonists (strong and weak). Through this protocol, it has shown that the studied purified saponins’ mixtures of Astragalus corniculatus and Astragalus glycyphylloides contain potential lead structures for PPARγ-mediated prevention and treatment of metabolic syndrome by weak partial agonism.
In silico approaches direct the efforts of researchers toward the most promising lead structures and build a bridge between theory and experiment, allowing both the prediction of unknown modes of action and the explanation of the molecular mechanism of effects already observed. The developed protocol for in silico prediction of possible metabolic transformations after oral administration of active molecules, their toxicity profile and potential therapeutic modes of molecular action, allows for a rapid and effective screening of a large number of molecules, preliminary outlining those having optimal potential to serve as scaffolds for development of medicines, nutritional supplements, or as components of new functional foods.
Researchers are seeking cooperation in the field of research and development to assist in the evaluation of medicines, foods and raw materials with a focus on new active molecules of natural origin; exchange of experience and good practices in the field of regulatory frameworks relevant to the subject under technical cooperation agreement with companies or research centres, in order to make further progress in protocol development. Finally, researchers are seeking investors interested in implementing new approaches for the prevention / therapy of metabolic syndrome through financial agreements.