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Design and synthesis of a potential orexin receptor OX2R modulator with the use of in silico methods
Kárová, Barbora ; Doležal, Rafael (advisor) ; Kolář, Karel (referee)
Orexinergic nervous system is a complex of neurons playing a significant role in managing sleep cycle and food intake. Orexin neurons situated in the lateral hypothalamus produce orexin neuropeptides A and B, which interact with two orexin receptors in a broad range of neurons in the brain. A reduced production of these neuropeptides due to the loss of orexin neurons is the cause of a specific and rare disease narcolepsy, which is currently incurable. A significant milestone in terms of drug research and development against narcolepsy is a study of Takashi Nagaraha's scientific group (2015), which was the first one to synthesize a non-peptidic agonist of the orexin 2 receptor (OX2R) that has inspired further design of new drug candidates with an increased chance to reach the clinical practice. This Bachelor Thesis is focused on the design and organic synthesis of a novel OX2R agonist with a 2-deoxystreptamine substructure and follows the Nagahara's study using rational and computer-aided drug design. The theoretical part is dedicated to the literature review of this issue, the practical part focuses on the design of 11 ligands using in silico and medicinal chemistry methods. The organic synthesis was then proposed, based on a retrosynthetic analysis, for the final candidate with the optimal...
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HLA complex and association with autoimmune diseases
Karasová, Alexandra ; Slavčev, Antonij (advisor) ; Šírová, Milada (referee)
Autoimmune diseases are serious and sometimes life-threatening disorders that affect approximately 5 % of the world population and therefore represent a major socio-medical problem. The HLA complex is the best studied part of the human genome that encodes the HLA antigens, whose function is to present peptides to immune system (T-lymphocytes). During the study of the HLA complex it has been found that certain HLA antigens are strongly associated with the occurence of autoimmune diseases, despite the great progress in clarifying disease etiopathogenesis the mechanism of these associations is, however, not fully explained. Sometimes the association of autoimmune disease with the HLA complex is very strong, such as in ankylosing spondylitis or celiac disease, while in other diseases the association is relatively weak, suggesting a role of other genetic and / or environmental factors. The aim of this work is to briefly explain the structure and function of the HLA complex and its association with some severe autoimmune diseases.
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