In silico screening of neuronal nitric oxide synthase enzyme inhibitors

dc.contributor.advisorYelekçi, Kemalen_US
dc.contributor.authorYelekçi, Kemal
dc.date.accessioned2019-07-12T08:39:40Zen_US
dc.date.available2019-07-12T08:39:40Zen_US
dc.date.issued2014en_US
dc.departmentEnstitüler, Lisansüstü Eğitim Enstitüsü, Hesaplamalı Biyoloji ve Biyoinformatik Ana Bilim Dalıen_US
dc.department-tempKadir Has University : Graduate School of Science and Engineering: Computational Biology and Bioinformaticsen_US
dc.description.abstractThree closely related isoforms of nitric oxide synthases (NOS) catalyze an important secondary messenger nitric oxide (NO) synthesis through oxidation of L-arginine to L-citrulline. These three NOS isoforms takes parts in different tissues for various physiological and pathological processes. Neuronal NOS (nNOS) produce NO in central and peripheral nervous system endothelial NOS (eNOS) plays role in endothelial cells and NO in macrophage cells is produced by inducible NOS (iNOS). Excessive NO production in nervous cells following pathological conditions is observed. Dysregulation of NO therefore may force NO to act as a neurotoxin that causes several neurodegenerative diseases including Parkinson’s Alzheimer’s Huntington’s diseases. Considering all these facts developing a selective and good potential inhibitor for nNOS is a compulsory task to achieve. However among all APPE isoforms there is high active site conservation so that no drug that shows these desired properties has yet been designed and developed.in this present work virtual screening techniques were applied to design selective nNOS inhibitors. Molecular modeling studies were done using already known crystal structures of all three isoforms. First of all to find primary lead candidates several hundred compounds were screened via ZiNCv12 lead library. Then modifications were done on the selected scaffolds via de novo design method to derive our inhibitor candidates. AutoDock 4.02 docking virtual tool was employed for docking and scoring of inhibitor candidates. inhibition constants and best pose predictions of docked ligands within the active sites of three isoforms were considered for further examinations and comparison analysis. Already bound ligands in downloaded experimentally determined X-ray structures of all isoforms were re-docked to crosscheck our studies. in this thesis two lead scaffolds among all and 22 inhibitor candidates derived from these two scaffolds were selected to discuss for optimization for further development of best potential and selective inhibitor for nNOS. -- Abstract'tan.en_US
dc.description.abstractThree closely related isoforms of nitric oxide synthases (NOS) catalyze an important secondary messenger nitric oxide (NO) synthesis through oxidation of L-arginine to L-citrulline. These three NOS isoforms takes parts in different tissues for various physiological and pathological processes. Neuronal NOS (nNOS) produce NO in central and peripheral nervous system, endothelial NOS (eNOS) plays role in endothelial cells and NO in macrophage cells is produced by inducible NOS (iNOS). Excessive NO production in nervous following pathologic conditions is observed and dysregulation of NO may force NO to act as a neurotoxin that causes several neurodegenerative diseases including Parkinson's, Alzheimer's, Huntington's diseases. Considering all these facts, developing a selective and good potential inhibitor for nNOS is a compulsory task to achieve. However, among all isoforms there is high active site conservation so that no drug that shows these desired properties has yet been designed and developed. In this present work, virtual screening techniques were applied to design selective nNOS inhibitors. Molecular modeling studies were done using already known crystal structures of all three isoforms. First of all, to find primary lead candidates, several hundred compounds were screened via ZINCv12 lead library. Then, modifications were done on the selected scaffolds via de novo design method to derive our inhibitor candidates. AutoDock 4.02 docking virtual tool was employed for docking and scoring of inhibitor candidates. Inhibition constants and best pose predictions of docked ligands within the active sites of three isoforms were considered for further examinations and comparison analysis. Already bound ligands in downloaded experimentally determined X-ray structures of all isoforms were re-docked to crosscheck our studies. In this thesis two lead scaffolds among all and 22 inhibitor candidates derived from these two scaffolds were selected to discuss for optimization for further development of best potential and selective inhibitor for nNOS.en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12469/2351
dc.identifier.yoktezid360948en_US
dc.language.isoenen_US
dc.publisherKadir Has Üniversitesien_US
dc.relation.publicationcategoryTezen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectNitric Oxide Synthaseen_US
dc.subjecteNOSen_US
dc.subjectiNOSen_US
dc.subjectnNOSen_US
dc.subjectde novo designen_US
dc.subjectDockingen_US
dc.subjectIn silico screeningen_US
dc.subjectNitrik oksit sentazen_US
dc.subjectde novo dizaynen_US
dc.subjectİlaç hedeflendirmesi (docking)en_US
dc.subjectin silico taramaen_US
dc.titleIn silico screening of neuronal nitric oxide synthase enzyme inhibitorsen_US
dc.typeMaster Thesisen_US
dspace.entity.typePublication
relation.isAuthorOfPublication9407938e-3d31-453b-9199-aaa8280a66c5
relation.isAuthorOfPublication.latestForDiscovery9407938e-3d31-453b-9199-aaa8280a66c5

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