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Interaction of small molecules with proteins in silico
Kučera, Tomáš ; Korábečný, Jan (advisor) ; Jampílek, Josef (referee) ; Holas, Ondřej (referee)
Computational methods are increasingly used in biomedical research, including toxi- cological research. They are used to search for new molecules for a particular phar- macological target or to optimize the properties of known active molecules. The main methods used in these areas are molecular docking and molecular dynamics. New reactivators of butyrylcholinesterase inhibited by nerve agents were sought by methods of virtual screening. This reactivators would be applicable in prophylaxis and therapy of nerve agents poisonings. By combining the techniques of semi-flexible and flexible docking, two new structures were proposed that should specifically re- activate the inhibited butyrylcholinesterase. In addition, a virtual screening of cyclophilin D inhibitors was performed. These compounds could be used as drugs for Alzheimer's disease. Based on the availability of a huge number of crystallographic data, we decided to use a pharmacophore for the primary screening of a large database of small molecules. Molecular docking was employed in the second search phase. At the same time, we focused on the physicochemical properties of molecules. Four ligands have been found that should be inhibitors of cyclophilin D bioavailable in the central nervous system. Flexible molecular docking was used to optimize the...
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Relationship between Structure and Biological Activity of new Modulators of Acetylcholinesterase
Komlóová, Markéta ; Doležal, Martin (advisor) ; Kuneš, Jiří (referee) ; Jampílek, Josef (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Dpt. of Pharmaceutical Chemistry and Drug Control Student: Mgr. Markéta Komlóová Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Title of Doctoral Thesis: Relationship between structure and biological activity of new modulators of acetylcholinesterase This work focuses on the preparation of peripherally acting AChE inhibitors as a potential treatment of myasthenia gravis. These compounds could also be used as a pre- treatment of poisoning by organophosphorus AChE inhibitors. They can occupy the active site of an enzyme making it inaccessible for irreversible inhibitors. Compounds used in this indication should fulfill these requirements: inhibit efficiently AChE (standards currently used in the treatment were chosen for the comparison of the inhibitory efficacy), have selective effect on AChE and not to cross the blood-brain barrier in order to lower the possible side effects. Six series of bisquaternary compounds were prepared. Their inhibitory ability was determined in vitro against human erythrocyte or recombinant AChE and human plasmatic BChE. According to inhibitory ability values acquired, a structure - activity relationships were investigated in every series. A few compounds with significant affinity towards...
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Examination of Potential Ligands of the Constitutive Androstane Receptor CAR
Zadák, Vojtěch ; Pávek, Petr (advisor) ; Jampílek, Josef (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Vojtěch Zadák Supervisor: Doc. PharmDr. Petr Pávek, Ph.D. Title of rigorous thesis: Examination of potential ligands of the constitutive androstane receptor CAR Year of completion: 2010 The constitutive androstane receptor - CAR is a representative of nuclear receptors that form a super-family of ligand-activated transcription factors regulating expression of target genes. In the last decade, CAR was mainly investigated in connection with an induction of biotransformation enzymes by remedies or other xenobiotics but in the past few years the research has also concentrated on a role of this receptor in hormone, lipid and energy homeostasis. Recently, there have been revealed some new important metabolic functions of CAR that may establish this "xenobiotic receptor" as a new therapeutic target for treatment of type 2 diabetes, obesity and dyslipidemia. The aim of this experimental rigorous thesis has been the examination of potential ligands of the human CAR (hCAR) from a given group of 16 chemicals with a defined structure. Using methods gene reporter assay, two-hybrid assay and one-hybrid assay we have tested this group from the perspective of an interaction with hCAR. The...
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