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Natural product-based modulation of metabolic syndrome: combining in silico and in vivo methods to investigate the potential role of the nuclear receptor PPARγ

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Partner keyword: 
Computational Chemistry and Modelling
Medical Technology / Biomedical Engineering
Pharmaceutical Products / Drugs
Biochemistry / Biophysics
Protein Engineering
Biochemistry / Biophysics
Pharmaceuticals/fine chemicals
Research and experimental development on biotechnology


Bulgarian research team offers computational modelling approaches to predict the pharmacokinetic and pharmacodynamic profiles of small molecules. It allows fast screening and prioritization of compounds based on evaluation of metabolism and toxicity associated with oral administration of a molecule and pharmacological potential of the molecule for the prevention / therapy of metabolic syndrome. Researchers are looking for technical cooperation agreement and/or financial agreement.



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.

Advantages & innovations

Cooperation plus value: 
The combination of in silico approaches with in vivo assays for the interdisciplinary study of purified saponins’ mixtures and sapogenins of Astragalus corniculatus and Astragalus glycyphylloides, as valuable natural resources for modulating metabolic disorders. Specificity in the design of the in silico screening protocol is the combination of the prediction of possible metabolites of natural compounds and their potential molecular mechanism of therapeutic action by computer simulation of their interaction with target protein in the human body. Currently, prior to the stage of in vivo studies, researchers rarely investigate the molecular mechanism of action of possible physiologically active metabolites that could be formed in the body by oral administration of drugs. Another feature of the protocol is the discrimination of individual subclasses of PPARγ partial agonists (strong and weak). Thanks to the combined in silico protocol developed, it was able to predict at an early stage the potential for anti-diabetic action of saponins from Astragalus corniculatus and Astragalus glycyphylloides, potentially based on modulation of PPARγ activity. This protocol allows for a preliminary assessment of the pharmacological activity of compounds and their possible metabolites, thereby helping to more effectively prioritize potential therapeutic molecules for subsequent analyses.

Stage of development

Cooperation stage dev stage: 
Under development/lab tested

Partner sought

Cooperation area: 
- Type of partner sought: Enterprises, research centers or investors; - Specific area of activity of the partner: pharmaceutical and food production industries; - Task to be performed: implementation of the protocol for the needs of the production of medicines, nutritional supplements or functional foods based on leading structures from natural origin. The Bulgarian research team is looking for: • Pharmaceutical companies or research institutions to further co-development of the protocol; • Companies or investors to implement the protocol.

Type and size

Cooperation task: 
SME 11-50,R&D Institution,SME <10,>500 MNE,251-500,SME 51-250,>500