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Development and prevalidation of predictive models for catechol drug conjugation and their evaluation for rational drug design

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For a realistic catechol drug design

The discovery and development of a new drug for the treatment of neurological and mental illnesses is mainly grounded on studying the metabolic interactions between catechol drugs and neurotransmitters. This breakthrough modelling of catechol drug conjugation may be used in drug metabolism studies for a rational drug design.

Health

Being one of the major cleansing pathways in our bodies, glucuronidation is a chemical reaction where a water-soluble substance in the body is combined with a harmful material and removes it from the body. Since most chemical reactions in the body are reversible, those harmful compounds that would normally be bound to inert molecules to be removed from the body are permitted to go free, potentially causing damage to the cells. Glucuronidation is involved in competing for conjugation of catechol-derived compounds, where participants have expression systems for most cloned human, highly specialised enzymes. With the aid of biochemistry and biotechnology, the project resulted in a complete study of the two major metabolic competent cells, in order to determine their catalytic activity in the catechols glucuronidation process. Initially, the Chinese hamster lung cells were generated and, by employing antibiotics for selecting the clones, the transfection of the cells was performed which resulted in an increased production of catalytically active proteins. These proteins are included in the glucuronidation of toxic substances, such as carcinogens and pesticides as well as nonsteroidal anti-inflammatory drugs. Measuring the activity kinetics, the amount of protein produced was determined and the expression of the recombinant enzymes was monitored. The most productive and stable clones were selected, stored and processed for investigation of the in vitro glucuronidation of catechols. Since the expression showed stability over time, recombinant enzymes were continuously supplied. Moreover, they can also be used for assessing bioavailability, drug metabolism and toxicity of drugs and chemicals, as well as drug-drug interactions. Furthermore, the expression can be employed for the study of the structure and the function of these membrane proteins. The ability of catechols to induce the specific enzymes is studied in human hepatocytes and in vivo in rats. Since the metabolic rates and the possible interactions of catechol compounds can be predicted before synthesis, the expression can be used for the evaluation of the efficacy and safety of catechol drug candidates initiating a new era in the field of drug discovery and development.

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