Browsing by Author "Kayrak, Nurdan"

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    Master Thesis
    In Silico Design of Selective Neuronal Nitric Oxide Synthase Inhibitors in Order To Prevent Neurodegenerative Diseases
    (Kadir Has Üniversitesi, 2013) Kayrak, Nurdan; Yelekçi, Kemal
    Nitric Oxide syntheses (NOS) are the family of enzymes which catalyzes the oxidation L-Arginine amino acid to nitric oxide molecule (NO) L-citrulline. Mammals contain three different NOS isozymes: Neuronal NOS (nNOS, in the brain), inducible NOS (iNOS, in macrophage cells), endothelial NOS (eNOS, the inner walls of blood vessels). Nitric Oxide (NO) is an important messenger molecule, which regulates several physiological functions in cardiovascular system and neuronal cells in the brain. Indeed, NO is a free radical gaseous molecule under normal conditions and highly toxic substance to our cells. In our body, it is produced locally at proper concentration at proper time. In endothelial cells, it relaxes smooth muscle causing to decrease blood pressure. Macrophage cells generate NO as an immune defense system to destroy microorganisms and pathogens. In our brain under certain pathological conditions after a certain ages produced excessive NO, causes tissue damage and oxidative stress. This leads are a variety of neurodegenerative diseases, such as Alzheimer's disease, rheumatoid arthritis and Parkinson's diseases. For this reason, it is important to inhibit selectively neuronal isozymes of NOS, nNOS in the brain. Three isozymes show extraordinarily structure similarities hindering the selective inhibitor design. In the literature there are many outstanding studies, however there has not being developed any drug which accomplished the required affinity and selectivity. Neurodegenerative diseases were very common death cause after cardiovascular diseases and cancer in the developed countries. We plan to use computer modeling based on the known crystal structure of three NO isozymes. In this project computationally, we developed, highly selective nNOS inhibitors via in silico screening. The inhibitors whose experimental inhibition values reported up to now were tested within our prepared model NOS isozymes. The obtained computational binding constants were compared with literature experimental values. The enzymes whose experimental values agreed with computational values were chosen for further studies. First, several suitable scaffolds (leads) were determined from lead library of ZINC database. These leads were optimized using fragment library of ZINC and Accelrys in the nNOS active site. The new selective and potent inhibitors were determined as a result of in silico screening. The inhibitors binding energy and inhibition constants toward nNOS, eNOS and iNOS enzymes are reported. In the future project, a collaborative work is going to be searched for the synthesis and enzymatic work of these determined inhibitors.
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    Article
    Citation Count: 7
    In Silico Identification of Novel and Selective Monoamine Oxidase B Inhibitors
    (SPRINGER WIEN, 2013) Yelekçi, Kemal; Büyüktürk, Bora; Kayrak, Nurdan
    Monoamine oxidases (MAO) A and B are flavin adenine dinucleotides containing enzymes bound to the mitochondrial outer membranes of the cells of the brain liver intestine and placenta as well as platelets. Recently selective MAO-B inhibitors have received increasing attention due to their neuroprotective properties and the multiple roles they can play in the therapy of neurodegenerative disorders. This study was based on 10 scaffolds that were selected from more than a million lead compounds in the ZINCv12 lead library for their structural and physicochemical properties which inhibit MAO-B. Utilizing ZINC and Accelrys 3.1 fragment-based libraries which contain about 400 thousand fragments we generated 200 potential candidates. GOLD LibDock and AutoDock 4.02 were used to identify the inhibition constants and their position in the active sites of both MAO isozymes. The dispositions of the candidate molecules within the organism were checked with ADMET PSA 2D (polar surface area) against ADMET AlogP98 (the logarithm of the partition coefficient between n-octanol and water). The MAO-B inhibition activities of the candidates were compared with the properties of rasagiline which is known to be a selective inhibitor of MAO-B.
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    Research Project
    Citation Count: 3