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Protein Family Based Approach in Drug Discovery : Cytochrome P450

Mercredi 26 septembre 2018 11:00 - Duree : 1 heure
Lieu : ILL4, seminar room, first floor - 71 avenue des Martyrs - Grenoble

Orateur : Andrei A. GILEP (Institute of Bioorganic Chemistry, NASB, Minsk, Belarus)

Cytochromes Р450 (Р450) are membrane bound hemeproteins involved in biosynthesis of bioactive molecules and metabolism of drugs. Impairment in the expression of P450s can cause breast and prostate cancer, resistant hypertension, chronic kidney disease, etc. This enzymes are also involved in the biotransformation of most foreign substances, including 70–80% of all drugs in clinical use. Moreover, this type of enzymes plays an essential role in metabolic functions of different pathogens.

Therefore, P450s are important targets for generation of new drugs for treatment of cancer, cardio-metabolic and endocrine disorders as well as drug-resistant forms of tuberculosis and mycosis. However these enzymes are challenging target for rational drug design : membrane nature for this hemeprotein ; require redox partners for functional assay ; high dynamic flexibility of substrate access channel and the active site ; co-translational folding (impossible to refold P450). As a result, it is impossible to predict substrate or inhibitor from primary structure of P450s.

Based on our scientific achievements we have developed a unique technological platform designed for P450-targeted drug discovery based on integration of scientific achievement in structural biology and enzymology as well as the use of bioinformatics, experimental and technological practices of synthesis the molecules with desired properties. Our research focused on understanding of molecular mechanism of substrate recognition, binding and catalysis of sterols and eicosanoids modifying P450s as well a structure-functional study of mycobacterial cytochromes P450 involved in biosynthesis and metabolism of bioactive lipids. This research provides valuable tool for P450-targeted rational drug design.

Contact : mader@ill.fr

Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (ILL)
Nature évènement : (Séminaire)
Evènement répétitif : (General ILL Seminar - College 8)
Site de l'évènement : Polygone scientifique

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