Thesis supervisor: Zoltán Varga
Location of studies (in Hungarian): Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen Abbreviation of location of studies: DEBSI
Description of the research topic:
In excitable cells action potentials are initiated by voltage-gated Na+ channels (NaV1.1-1.9). NaV1.1-1.3 and 1.6 are mostly expressed in neurons in the central, while NaV1.7-1.9 in the peripheral nervous system. NaV1.4 functions in skeletal muscles and 1.5 in the heart. Their wide tissue distribution and critical role in excitable cells make NaV channels attractive pharmacological targets. Many compounds are used successfully in clinical practice to suppress pain, treat arrhythmias, myotonic disorders, periodic paralyses, epilepsy and migraine. Despite these applications and extensive efforts to develop high affinity and selectivity modulators, most compounds in use are not ideal drugs as they have low therapeutic indexes and multiple serious side effects due to their action on off-target NaV subtypes. Thus, there is still a great need for new lead compounds, preferably with novel sites and mechanisms of action, which may be structurally and functionally more selective than the currently used ones.
The aim of the project is to develop new NaV channel modulator lead compounds by rational design that could be eventually advanced to become therapeutically effective drugs for NaV channel-associated channelopathies. Starting with a small library of molecules known to affect NaV channels we will explore their mechanism of action and binding site, isoform and functional selectivity, the effect of auxiliary subunits and then apply in silico modeling to explore interactions and design modifications to improve their properties. The modified molecules will then be synthesized and further developed in an iterative fashion.
Required language skills: English intermediate level Number of students who can be accepted: 2
Deadline for application: 2021-11-15
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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