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Development of pharmacophore-guided molecular docking protocol for design of SARS-CoV-2 main protease inhibitors
Klenor, Mikuláš ; Lepšík, Martin (advisor) ; Riedlová, Kamila (referee)
Covid-19 is a highly contagious potentially life-threatening disease caused by the SARS-CoV-2 coronavirus. The virus is responsible for a global pandemic and has claimed over 6 million human lives between years 2020 and 2022. To limit the spread of SARS-CoV-2, numerous vaccines have been developed and applied. For already infected individuals, antiviral drugs are applied. An important validated target is the main protease of SARS-CoV-2 (Mpro ). Although thousands of inhibitors have been prepared and one is used in clinical practice (sold under the name of Paxlovid), improved computational protocols to design new active compounds are needed. The computational approach used here is based on pharmacophores. By curating and inspecting 298 structures of Mpro /inhibitors complexes retrieved from the Protein Data Bank (PDB), we have generated six distinct pharmacophores featuring different binding modes. With their aid, we have carried out molecular docking, whose effectiveness was evaluated by measuring root-mean-square deviation (RMSD) of the generated poses with respect to the native conformations. The routine captured 177 out of 213 ligands naturally binding to the active site of the protein with 127 (72% of the captured) generated with RMSD within 2 Å relative to the native conformation....
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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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Molecular Docking Study Of Potential Drug Candidates Against Borreliosis
Koščová, Pavlína
Lyme borreliosis is one of the most common tick-borne infections, for which there is an extensive need to find a new drug. For this purpose our in silico docking study was carried out to identify drug-likeness of chosen small molecules – potential borreliosis drugs. Its results revealed that BesA compound (C2 form) – a membrane fusion protein present in Borrelia burgdorferi, can play a significant role as a possible drug target compound and therefore it should be further examined in development of potential drugs for Lyme borreliosis treatment.
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Mechanisms involved in sodium uptake activation by the Tumor Necrosis Factor-derived TIP peptide
DULEBO, Alexander
The Tumor Necrosis Factor derived-TIP peptide is a small 17 amino acids cyclic peptide with lectin-like activity, that possesses several therapeutically relevant biological activities, among which is activation of alveolar liquid clearance in both healthy and injured lungs in vivo. Accumulation of fluid in the lungs? alveoli and interstitial spaces is a life-threatening condition called pulmonary edema. The mortality rate due permeability pulmonary edema, accompanied by a dysfunction of the alveolar/capillary barrier, is high because no effective treatment lacking side effects exists nowadays. It is known that the TIP peptide is able to activate vectorial Na+ transport ? which mediates lung liquid clearance. However, the mechanism of action of remains elusive. The aim of this thesis was to investigate the initial steps of interaction between the TIP peptide and airway epithelial cells. Numerous novel methods and single-molecule techniques were used to unravel: (i) how the TIP peptide interacts with the molecules on the apical side of the lung epithelial cells; (ii) whether the TIP peptide need to be internalized inside of the cells to trigger its effects; (iii) the nature of the interaction between the TIP peptide and its putative receptor(s); (iv) the putative receptor(s) for the TIP peptide on the apical surface of the lung epithelial cells.
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