To see the other types of publications on this topic, follow the link: Structure-activity relationship (Biochemistry).
Dissertations / Theses on the topic 'Structure-activity relationship (Biochemistry)'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 37 dissertations / theses for your research on the topic 'Structure-activity relationship (Biochemistry).'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Nahas, Roger I. "Synthesis and structure-activity relationship of a series of sigma receptor ligands." Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/4840.
Full textAbstract:
Thesis (Ph. D.)--University of Missouri-Columbia, 2007.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on February 26, 2008) Vita. Includes bibliographical references.
2
Lanevskij, Kiril. "Absorption and Tissue Distribution of Drug-Like Compounds: Quantitative Structure-Activity Relationship Analysis." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2011. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2011~D_20111003_114235-89858.
Full textAbstract:
The objective of this work was to develop mechanistic quantitative structure activity relationship models that would facilitate the assessment of drug properties related to their absorption and distribution in the body. The analysis involved several parameters reflecting the rate of passive diffusion across brain endothelium and intestinal epithelium, and thermodynamic constants related to drug distribution between plasma and tissues. Permeation through cellular transport barriers was modeled by nonlinear equations relating the passive diffusion rate to physicochemical properties of drugs: lipophilicity, ionization, hydrogen bonding potential and molecular size. It was demonstrated that brain endothelium and intestinal epithelium exhibit a quantitatively similar pattern of permeability-ionization dependence – ionized species permeate 2-3 orders of magnitude slower than neutral molecules. Analysis of tissue to plasma partitioning data revealed the necessity to split original experimental values into separate terms reflecting plasma and tissue binding strength. Drugs’ affinity to tissues could then be described by their lipophilicity, whereas detrimental effect of ionization was only observed for acidic drugs. Finally, it was shown that a linear combination of quantitative blood-brain barrier transport parameters allows classifying drugs according to their access to central nervous system with 94% overall accuracy.Šiame darbe pristatomi mechanistiniai kiekybinio struktūros ir aktyvumo ryšio modeliai, skirti vaistinių junginių savybių, charakterizuojančių jų absorbciją ir pasiskirstymą organizme prognozavimui. Nagrinėjama keletas parametrų, apibūdinančių paprastos difuzijos per biologines membranas greitį, taip pat termodinaminės konstantos, aprašančios vaistų pasiskirstymą tarp kraujo plazmos ir audinių. Ląstelinių pernašos barjerų pralaidumas buvo modeliuojamas netiesinėmis lygtimis, siejančiomis paprastos difuzijos greitį su vaistų fizikocheminėmis savybėmis, tokiomis kaip lipofiliškumas, jonizacija, vandenilinių ryšių sudarymo potencialas ir molekulių dydis. Nustatyta, kad smegenų endotelyje ir žarnyno epitelyje stebima panašaus pobūdžio difuzijos greičio priklausomybė nuo jonizacijos – katijonai ir anijonai difunduoja atitinkamai 2 ir 3 eilėmis lėčiau už neutralias molekules. Pademonstruota, kad analizuojant vaistų pasiskirstymo tarp audinių ir kraujo duomenis, būtina paversti pradines eksperimentines vertes kitais dydžiais, atspindinčiais vaistų jungimosi prie plazmos ir audinių komponentų stiprumą. Vaistų giminingumas audiniams gali būti aprašytas jų lipofiliškumu, o neigiama jonizacijos įtaka stebima tik rūgštiniams junginiams. Taip pat parodyta, kad vaistų pernašos per hematoencefalinę užtvarą kiekybinių parametrų tiesinė kombinacija leidžia 94% tikslumu klasifikuoti vaistus pagal jų prieinamumą centrinei nervų sistemai.
3
DeBord, Michael. "Synthesis, characterization, and anti-cancer structure-activity relationship studies of imidazolium salts." University of Akron / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=akron1489414733025495.
Full text
4
Pandit, Bulbul. "Study of structure activity relationship of analogs derived from SU-5416 and thalidomide and mechanism of antiproliferative activity." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1187127289.
Full text
5
Azizeh, Bassem Yousef. "Structure-activity relationship analysis: Developing glucagon agonists and antagonists for studies of glucagon action in normal and diabetic states." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/282252.
Full textAbstract:
Several glucagon analogues containing substitutions in the N-terminal region, in particular residues 1, 5, 6, 9 and 10 (histidine, threonine, phenylalanine, aspartic acid and tyrosine, respectively), were synthesized. In addition four β-methylphenylalanine isomers were introduced at position ten to assess the role of these topographical modifications on hormone activity, and to study the effect of constraint and biased conformational preferences of the side chain moieties on biological activity. All the analogues were synthesized by solid-phase methodology, purified to homogeneity by reverse-phase high-performance liquid chromatography, and characterized by electrospray mass spectroscopy, amino acid analysis and thin layer chromatography. Following characterization they were analyzed using rat liver plasma membranes for receptor-binding affinity as well as their ability to stimulate adenylate cyclase. Structure-activity relationship analysis provided critical information about the conformational, chemical and structural properties of amino acid residues required for receptor recognition and signal transduction in the glucagon sequence. His¹ was confirmed to operate along with Asp⁹ for the activation and binding to the glucagon receptor. These new findings should permit the design of more pure and potent glucagon receptor antagonists by focusing on the role of Phe⁶ and other residues in the N-terminal region. A newly developed assay for examining low levels of cAMP accumulation in response to glucagon antagonists, agonists and partial agonists was developed. Previously reported glucagon receptor antagonists had partial agonist activity in rat hepatocytes. This assay system, in conjunction with binding and adenylate cyclase studies in both hepatocytes and liver plasma membranes, redefines the major characteristics of pure glucagon antagonists. The most potent glucagon receptor antagonist [des-His¹, des-Phe⁶, Glu⁹]glucagon-NH₂ was studied using conformational analysis and 2D NMR techniques to analyze the secondary structure of the analogue. Proton resonance assignments using COSY, NOESY and TOCSY in d₆-DMSO were made.
6
Hall, Sara M. "Bradykinin Ligands and Receptors Involved in Neuropathic Pain." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/578606.
Full textAbstract:
Neuropathic pain is a prevalent disease with no effective, safe treatments and limited knowledge on the mechanisms involved. One target for neuropathic pain treatment may be the blockade of Dynorphin A (Dyn A). Dyn A is a unique endogenous ligand that possesses well-known neuroinhibitory effects via opioid receptors and neuroexcitatory effects that are mediated through the bradykinin 2 receptors (B2Rs). Extensive SAR was carried out to develop a ligand for the blockade of the excitatory actions of Dyn A at the B2R. A lead ligand was able to block Dyn A-induced hyperalgesia in naïve animals and was effective in a neuropathic pain model. However, the ligand was susceptible to enzymatic degradation. In an effort to increase the stability, modifications of the ligand using non-natural amino acids were performed. Analogues substituted at or near the N-terminus with a D-isomer retained binding at the receptor as well as provided a large increase in stability. These ligands were also found to be non-toxic in a cell toxicity assay. Dyn A has been found to not activate the classical signaling of the B2R, PI hydrolysis or Ca²⁺ mobilization. In an effort to determine Dyn A's signaling, a study was done examining up-regulation of phosphorylated proteins. It was found that Dyn A did not activate; pERK, 7 PKC isoforms or PKA. A well known B2R antagonist, HOE140, was found to have low affinity at rat and guinea pig brain B2Rs but high affinity in the guinea pig ileum. Further examination revealed that this discrepancy in binding may arise from a different isoform of the B2R that has not been previously examined. To date, we have discovered Dyn A analogues that have high affinity for the B2R, are very stable, and have low toxicity. The signaling pathway is still not fully understood, but further studies are underway. Also, there is evidence that the B2R in which the analogues are interacting at may be a different form than what has previously been described. Targeting this different isoform of the B2R with our current stable ligands may provide beneficial therapeutics for the treatment of neuropathic pain without the cardiovascular liabilities.
7
Andersson, Karl. "Characterization of Biomolecular Interactions Using a Multivariate Approach." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4322.
Full text
8
Jennings, Megan Christina. "Bioorganic Investigation of Quaternary Ammonium Compounds: Probing Antibacterial Activity and Resistance Development with Diverse Polyamine Scaffolds." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/434038.
Full textAbstract:
ChemistryPh.D.
Quaternary ammonium compounds (QACs) have long served as lead disinfectants in residential, industrial, and hospital settings. Their simple yet effective amphiphilic nature makes them an ideal class of compounds through which to explore antibacterial activity. We have developed novel multiQAC scaffolds through simple and cost-efficient syntheses, yielding hundreds of diverse compounds strategically designed to examine various aspects of antibacterial and anti-biofilm activity, as well as toxicity. Many of these bis-, tris-, and tetraQACs display antibacterial activity 10 to 100 times greater than conventional monoQACs, and are among the most potent biofilm eradicators to date. Through analyzing their activity against several strains, we have uncovered and provided further evidence for key tenets of amphiphilic QAC bioactivity: a balance of hydrophobic side chains with cationic head groups generates optimal antibacterial activity, though toxicity to eukaryotic cells needs to be mitigated. Given their ubiquitous nature and chemical robustness, the overuse of QACs has led to the development of QAC resistance genes that are spreading throughout the microbial world at an alarming rate. These resistant strains, when found in bacterial biofilms, are able to persist in the presence of lead commercial QAC disinfectants, warranting the development of next-generation biocides. Several of our scaffolds were designed with QAC resistance machinery in mind; thus, we utilized these compounds not only as antibacterial agents but also as chemical probes to better understand and characterize QAC-resistance in methicillin-resistant Staphylococcus aureus (MRSA). Our findings support previous postulations that triscationic QACs would retain potency against QAC-resistant strains. Furthermore, we have identified monocationic and aromatic moieties, as well as conformational rigidity, as being more prone to recognition by the resistance machinery. Using our chemical toolbox comprised of QACs of various charge state and scaffold, we explored both the mechanism and scope of QAC-resistance by examining their structure-resistance relationship. Our holistic findings have allowed us to better understand the dynamics of this system towards the design and development of next-generation QACs that will: (1) allow us to better probe the resistance machinery, and (2) remain efficacious against a variety of microbial pathogens.
Temple University--Theses
9
Goff, Randal Donald. "Structure-Activity Studies of Glycosphingolipids as Antigens of Natural Killer T Cells." BYU ScholarsArchive, 2006. https://scholarsarchive.byu.edu/etd/942.
Full textAbstract:
Glycosphingolipids (GSLs), composed of a polar saccharide head and a lipophilic ceramide tail, are ubiquitous components of the plasma membrane of eukaryotic cells. They serve in many regulatory capacities and have antigenic properties towards natural killer T (NKT) cells of the innate immune system. Critical to the recognition of glycosylceramides by NKT cells are antigen presenting cells (APC), such as dendritic cells, which are responsible for binding, processing, and delivery of ligands to these lymphocytes. This event is mediated by CD1d, a major histocompatibility complex-like protein expressed on the surface of APCs, which binds GSL antigens by the ceramide moiety and presents the polar group to the T cell receptors of CD1d-restricted cells. The subsequent immune response involves NKT cell proliferation and emission of numerous cytokines, such as interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), resulting in the stimulation of the innate and adaptive immune systems through maturation of APCs, activation of T cells, and secretion of antibodies by B cells. To understand the structure-activity relationship between GSLs and NKT cell activity and the requirements for intracellular processing of antigens, analogs of the model compound alphaGalCer (KRN-7000) have been synthesized. These include fluorophore-appended 6”-amino-α-galactosylceramides and N-alkenoyl GSLs, such as PBS-57, a potent alphaGalCer surrogate useful in NKT cell stimulation studies. A nonantigenic beta-C-galactosylceramide has also been prepared as an inhibitor of these innate lymphocytes. To probe the potential for using NKT cells to bias the immune system between the proinflammatory TH1 response or the immunomodulatory TH2 mode, versions of alphaGalCer with shortened ceramides have been created. One of these truncated analogs, PBS-25, has successfully been cocrystallized with CD1d and the binary complex structure solved by X-ray crystallography. Synthetic glycosphingolipids derived from Novosphingobium capsulatum and Sphingomonas paucimobilis have also been made. In assays with classical Valpha14i/Valpha24i NKT cell lines, these Gram-negative bacterial antigens were recognized directly and specifically by host immune systems through CD1d-restriction, unlike GSL-deficient microbes (e.g., Salmonella typhimurium). A search for other GSL-bearing alpha-proteobacteria led to the discovery of another natural glycosphingolipid, an N-alkenoylphytosphingoid-alpha-galactoside, isolated from the outer membrane of Ehrlichia muris.
10
Trabbic, Christopher J. "Chemoenzymatic Synthesis of NAADP Derivatives: Probing the Unknown NAADP Receptor." University of Toledo Health Science Campus / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=mco1333749803.
Full text
11
Kress, Brian J. "Synthesis of Novel Small Molecule PPARδ Agonists for Controlling Mesenchymal Stem Cell Osteogenesis." University of Toledo Health Science Campus / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=mco1564751044043639.
Full text
12
Bottoms, Christopher A. "Bioinformatics of protein bound water." Diss., Columbia, Mo. : University of Missouri-Columbia, 2005. http://hdl.handle.net/10355/4188.
Full textAbstract:
Thesis (Ph. D.)--University of Missouri-Columbia, 2005.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (July 17, 2006) Vita. Includes bibliographical references.
13
Bruce, Craig L. "Classification and interpretation in quantitative structure-activity relationships." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11666/.
Full textAbstract:
A good QSAR model comprises several components. Predictive accuracy is paramount, but it is not the only important aspect. In addition, one should apply robust and appropriate statistical tests to the models to assess their significance or the significance of any apparent improvements. The real impact of a QSAR, however, perhaps lies in its chemical insight and interpretation, an aspect which is often overlooked. This thesis covers three main topics: a comparison of contemporary classifiers, interpretability of random forests and usage of interpretable descriptors. The selection of data mining technique and descriptors entirely determine the available interpretation. Using interpretable approaches we have demonstrated their success on a variety of data sets. By using robust multiple comparison statistics with eight data sets we demonstrate that a random forest has comparable predictive accuracies to the de facto standard, support vector machine. A random forest is inherently more interpretable than support vector machine, due to the underlying tree construction. We can extract some chemical insight from the random forest. However, with additional tools further insight would be available. A decision tree is easier to interpret than a random forest. Therefore, to obtain useful interpretation from a random forest we have employed a selection of tools. This includes alternative representations of the trees using SMILES and SMARTS. Using existing methods we can compare and cluster the trees in this representation. Descriptor analysis and importance can be measured at the tree and forest level. Pathways in the trees can be compared and frequently occurring subgraphs identified. These tools have been built around the Weka machine learning workbench and are designed to allow further additions of new functionality. The interpretability of a model is dependent on the model and the descriptors. They must describe something meaningful. To this end we have used the TMACC descriptors in the Solubility Challenge and literature data sets. We report how our retrospective analysis confirms existing knowledge and how we identify novel C-domain inhibition of ACE. In order to test our hypotheses we extended and developed existing software forming two applications. The Nottingham Cheminformatics Workbench (NCW) will generate TMACC descriptors and allows the user to build and analyse models, including visualising the chemical interpretation. Forest Based Interpretation (FBI) provides various tools for interpretating a random forest model. Both applications are written in Java with full documentation and simple installations wizards are available for Windows, Linux and Mac.
14
Spathelf, Barbara Marianne. "Qualitative structure-activity relationships of the major tyrocidines, cyclic decapeptides from Bacillus aneurinolyticus." Thesis, Stellenbosch : University of Stellenbosch, 2010. http://hdl.handle.net/10019.1/4001.
Full textAbstract:
Thesis (PhD (Biochemistry))--University of Stellenbosch, 2010.ENGLISH ABSTRACT: The need for alternative or supplementary treatments due to the global problem of microbial resistance towards conventional antimicrobials may be met by the development of novel drugs based on antimicrobial peptides. The antimicrobial peptides of interest to this study were the tyrocidines, cyclic decapeptides produced by Bacillus aneurinolyticus. Although these antimicrobial peptides were the first natural antibiotic to be discovered though a systematic search for antibacterial compounds, information regarding their bioactivity, structure-activity relationships, determinants of bioactivity and mode of action is limited. The aim of this study was to investigate the antibacterial and antiplasmodial activity, as well as to identify determinants of bioactivity modulation, of the natural tyrocidine library. The study indicated that the tyrocidines exhibit significant activity toward Gram-positive bacteria, notably Listeria monocytogenes, and the intraerythocytic parasite, Plasmodium falciparum. Both the antilisterial and antiplasmodial activity was found to be highly dependent on peptide identity and self-assembly. The antilisterial activity of the tyrocidines was shown to be associated with increased self-assembly within a membrane-like environment, which suggested that formation of lytic complexes within the bacterial membrane may play a crucial role in tyrocidine activity. In contrast to the observations for antilisterial activity, the antiplasmodial activity of the tyrocidines was shown to be associated with reduced self-assembly within a membrane-like environment, which suggested that the antiplasmodial activity of the tyrocidines is mediated by a mechanism other than the formation of lytic complexes within the target cell membrane. In addition to the influence of peptide identity and self-assembly, the bioactivity of the tyrocidines was found to be highly sensitive to environmental conditions, notably the presence of calcium. The antilisterial activity, as well as the mode of action, of the tyrocidines was also found to be highly sensitive to tyrocidine-Ca2+ complexation and the concomitant induction of higher-order structures. Tyrocidine-Ca2+ complexation was shown to greatly enhance antilisterial activity and change the mechanism of action from a predominantly membranolytic to an alternative, non-lytic mode of action. The results of this investigation suggest that the alternative mode of tyrocidine activity may be related to complexation with Ca2+. It is hypothesised that such complexation may either (1) promote tyrocidine-DNA complexation, and thus inhibition of transcription and/or replication; or (2) interfere with Ca2+ homeostasis, and thus influence vital cell functions. Overall, it may be hypothesised that tyrocidine activity and mode of action is modulated by a critical play-off between self-assembly, cation-complexation and membrane-interaction. As these modulators of activity are highly dependent on tyrocidine sequence/structure, the wide variety of tyrocidines found in the natural complex may allow for optimal interaction with and activity toward a variety of microbes.
AFRIKAANSE OPSOMMING: Die universele probleem van mikrobiese weerstand teen konvensionele antimikrobiese middels en die wêreld-wye noodsaaklikheid vir alternatiewe of bykomende behandeling mag deur die ontwikkeling van nuwe middels, gebasseer op antimikrobiese peptiede, vervul word. Die antimikrobiese peptiede van belang tot hierdie studie is die tirosidiene, sikliese dekapeptiede wat deur Bacillus aneurinolyticus geproduseer word. Informasie ten opsigte van die tirosidiene se bioaktiwiteit, struktuur-funksieverwantskap, determinante van bio-aktiwiteit en meganisme van aksie was beperk, alhoewel hierdie peptiede die eerste antimikrobiese peptiede was wat ontdek is deur ‘n sistematiese soektog vir antimikrobiese middels. Die doelwit van hierdie studie was die ondersoek van antibakteriële and antiplasmodiese aktiwiteit, sowel as om die determinante van bio-aktiwiteit modulering van die natuurlike tirosidienbiblioteek te ondersoek. Hierdie studie het getoon dat die tirosidiene merkwaardige aktiwiteit teenoor Gram-positiewe bakterië, in besonder Listeria monocytogenes het, asook teenoor die intra-eritrositiese parasiet, Plasmodium falciparum. Daar is bevind dat beide die antilisteriese en antiplasmodiese aktiwiteite hoogs afhanklik is van peptiedidentiteit en self-verpakking. Daar is gewys dat die antilisteriese aktiwiteit van die tirosidiene geassosieer is met verhoogde self-verpakking in ’n membraanagtige omgewing, wat ’n aanduiding is dat die vorming van litiese komplekse in die bakteriële membraan ’n kritiese rol in tirosidienaktiwiteit speel. Kontrasterend tot die waarnemings van antilisteriese aktiwiteit, is getoon dat die antiplasmodiese aktiwiteit van die tirosidiene geassosieer is met verlaagde self-verpakking in ’n membraanagtige omgewing. Dis ’n aanduiding dat die antiplasmodiese aktiwiteit van die tirosidiene gemediëer word deur ‘n ander meganisme en nie die vorming van litiese komplekse in die teikenselmembraan nie. Bykomend tot die invloed van peptiedidentiteit en self-verpakking, is daar bevind dat die bioaktiwiteit van die tirosidiene hoogs sensitief is vir die omgewing, in besonder die teenwoordigheid van kalsium. Daar is ook bevind dat die antilisteriese aktiwiteit, sowel as die meganisme van aksie, van tirosidiene hoogs sensitief is vir tirosidien-Ca2+ kompleksvorming en die gevolglike induksie van of hoër-orde strukture. Daar is gewys dat tirosidien-Ca2+ kompleksvorming die antilisteriese aktiwiteit drasties verhoog en dat die meganisme van aksie verander van ’n oorwegende membranolitiese meganisme na ’n alternatiewe nie-litiese meganisme van aksie. Die resultate van hierdie ondersoek het aangedui dat die alternatiewe meganisme van aksie van tirosidienaktiwiteit moontlik verband kan hou met kompleksvorming met Ca2+. Die hipotese is dat sodanige kompleksvorming moontlik of (1) tirosidien-DNA komplekvorming aanmoedig, en dus transkripsie en/of replikasie inhibibeer of (2) met Ca2+ homeostase inmeng, en sodoende lewensnoodsaaklike selfunksies beïnvloed. Die algemene hipotese is dat tirosidienaktiwiteit en meganisme van aksie deur ’n kritiese spel tussen self-verpakking, katioonkompleksvorming en membraaninteraksie gemoduleer word. Die wye verskeidenheid van tirosidiene, wat in die natuurlike kompleks gevind word, kan moontlik toelaat vir die optimale interaksie met, en aktiwiteit teenoor ’n verskeidenheid van mikrobes, aangesien die aktiwiteitmoduleerders hoogs afhanklik is van tirosidien struktuur/volgorde.
15
Lewis, David Francis Victor. "Molecular modelling and structure-activity relationships in the cytochrome P450 enzyme superfamily." Thesis, University of Bath, 2000. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268758.
Full textAbstract:
The cytochromes P450 constitute a superfamily of over 750 individual enzymes, present in species from all five biological kingdoms, which are primarily associated with the oxidative metabolism of a vast number and variety of organic compounds, both endogenous and exogenous. These haem-thiolate enzymes bind and activate dioxygen such that mono-oxygenation of the substrate occurs, with the concomitant production of a water molecule. There is considerable current interest in the P450 mono-oxygenase system due to its major involvement in the Phase I oxidations of pharmaceuticals and, also, because of an exogenous role in the metabolic activation of carcinogens and other toxic agents. Consequently, the P450s with their particular substrate specificities represent an important area for the application of structural modelling in the rationalization of drug metabolism, and for the evaluation of potential toxicity in novel chemicals. Before crystal structures of P450s were available, it was possible to determine the molecular and electronic characteristics of P450 substrates and inducers responsible for determining enzyme specificity using a combination of molecular orbital procedures and structural modelling techniques. These investigations led to the development of COMPACT, which is a method for the prediction of P450-mediated toxicity and carcinogenicity based on the structural properties of the compound concerned. The COMPACT technique has been shown to be over 70% concordant with rodent carcinogenicity bioassay data, and this was Subsequently found to be increased by the utilization of a structural alert progra.T1l which identifies direct-acting agents. However, in order to improve the scope of the COMPACT procedure such that the methodology can be applied to human P450 substrate specificity, it was necessary to derive three-dimensional models of the enzymes themselves. Extensive modelling studies on human P450s involved in drug metabolism appear to be entirely consistent with experimental observations, thus demonstrating the reliability of this approach
16
Chen, Jonathan Jun Feng. "Data Mining/Machine Learning Techniques for Drug Discovery: Computational and Experimental Pipeline Development." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1524661027035591.
Full text
17
Agyeman, Akwasi. "T box antiterminator-tRNA recognition elements /." View abstract, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3266062.
Full text
18
Janosi, Lorant. "Multiscale modeling of biomolecular systems." Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/4801.
Full textAbstract:
Thesis (Ph. D.)--University of Missouri-Columbia, 2007.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on February 14, 2008) Vita. Includes bibliographical references.
19
Fisher, Michael B. "The enzymology and mechanisms of cytochrome P450-catalyzed aliphatic desaturation /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/8158.
Full text
20
Huang, Hao-Hsin. "Structure-property behavior of hybrid materials incorporating oligomeric species with inorganic silicates by a sol-gel process." Diss., Virginia Polytechnic Institute and State University, 1988. http://hdl.handle.net/10919/53534.
Full textAbstract:
A sol-gel process has been utilized to develop novel hybrid materials incorporating organic and inorganic species. The objectives of this project were to study the feasibility of this new bridging route and, if successful, study the structure-property relationships of these new materials. In this thesis, tetraorthosilicate was used to combine with one of three types of oligomers, which included silanol terminated polydimethylsiloxane (PDMS), triethoxysilane endcapped polytetramethyleneoxide (PTMO), and PTMO with multiple triethoxysilane functional groups. The general reaction scheme was to first generate silanols from both components through the hydrolysis reaction, and then form the network structure by a co-condensation reaction with the silanol groups. The preparation of these hybrid materials was successful. Most of these hybrid materials were obtained without significant cracking problems with an initial TEOS loading up to 80 wt%, and the final products were always transparent.
For the PDMS containing systems, the tensile strength was always lower than 8 MPa. and the elongation at break was in the range of 5-25%. Dynamic mechanical results showed a bimodal tanδ behavior, which was attributed to two different physico-chemical environments of the oligomers: one was PDMS rich phase and one represented more dispersed PDMS oligomers. The dispersion of the oligomers increased with acid and silicate content of the system, and this postulation of better PDMS dispersion was strongly supported by the SAXS results which showed a systematic decrease in the mean square electron density fluctuation.
The mechanical properties of PTMO containing materials were considerably enhanced compared to the PDMS hybrid systems. Depending on the composition and oligomeric molecular weight, the tensile strength could reach 33 MPa. Also, the range of the elongation at break increased up to ca. 100%. The tanδ spectra showed a single, broad maximum at temperatures much higher than the Tg of pure PTMO oligomers, which indicated the absence of a pure oligomer phase. A broad maximum in the SAXS profile was observed in most cases, implying the existence of a correlation distance in these PTMO containing materials. To rationalize all the experimental observations, a schematic model was suggested which contains highly condensed TEOS clusters and mixed regions of partially condensed TEOS and PTMO. This model was further supported by swelling data and by agreement between the SAXS correlation length and the estimated PTMO end-to-end distance.
The systems prepared with PTMO possessing multiple triethoxysilane groups showed the most promising results in terms of mechanical properties. The tensile strength ranged from ca. 30 to 55 MPa., and the ambient modulus was nearly 10⁸ Pa. Also, a yield point was observed in some cases and was postulated to be an indication of partial continuity of the silicate phase.Ph. D.
21
Chang, Cheng. "In silico approaches for studying transporter and receptor structure-activity relationships." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1117553995.
Full textAbstract:
Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xvii, 271 p.; also includes graphics. Includes bibliographical references (p. 245-269). Available online via OhioLINK's ETD Center
22
Delfin, Dawn Athelsia. "A novel and potent antileishmanial agent in silico discovery, biological evaluation and analysis of its structure-activity relationships /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1180527456.
Full text
23
Kazmierski, Wieslaw Mieczyslaw. "Synthesis and hydrogen-1 NMR conformational analysis of potent and mu opioid receptor selective cyclic peptides: Topographical design utilizing a conformationally stable template." Diss., The University of Arizona, 1988. http://hdl.handle.net/10150/184454.
Full textAbstract:
There is a dogma in molecular biology that biological functions of peptides are determined by their structure ("function" code), coded in their primary structure ("structure" code). This work describes a new approach that attempts to elucidate these relationships by peptide topology design based on intriguing conformational properties of pipecolic acid based amino acids--like 1,2,3,4 tetrahydroisoquinoline (Tic). Opioid peptides, owing to the heterogeneity of opioid receptors, display a wide variety of physiological actions. The mu opioid receptor selective octapeptide I (D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂) is a model compound for topographical modifications induced by sequential substitutions by Tic residue. Thus, the closely related peptides I and II (Gly-D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂, obtained by coupling Gly residue to I) have contrasting affinities for the mu opioid receptor (IC₅₀ = 1.2 and 278 nM, respectively). Conformational analysis of I and II by means of 1D and 2D ¹H NMR spectroscopy allowed to determine dramatic differences in the side chain orientation of D-Tic in both peptides and to propose features of the bioactive conformation. The extended conformation of I (due to g(-) side chain conformation of D-Tic) is well recognized by the mu receptor in contrast to the folded conformation of II (due to a g(+) side chain conformation of D-Tic¹, that places the aromatic ring on the opposite side of the molecule), which is not. Peptide III (D-Phe-Cys-Tic-D-Trp-Orn-Thr-Pen-Thr-NH₂), featuring replacement of Tyr³ by Tic³, binds very weakly to the mu opioid receptor, due to rotation of the Tic aromatic side chain to the opposite side of the molecule (Tic side chain is in a g(+) conformation again). As these substitutions conserve the conformation of the backbone, constrained cyclic amino acids (picolic acid derivatives) can modify the topography of the peptide in a predictable manner, and (in conjunction with biological data) disclose structural elements of bioactive conformations. The mechanisms of pipecolic acid side chain rotamer selection, will be discussed in the context of design principles.
24
Breydo, Leonid P. "New mechanisms of DNA damage and non-covalent DNA binding by the antitumor antibiotic Leinamycin." free to MU campus, to others for purchase free online, 2002. http://wwwlib.umi.com/cr/mo/preview?3052153.
Full text
25
Mugabe, Benon E. Trawick Mary Lynn. "Structure-activity relationships and thermodynamics of combretastatin A-4 and A-1 derivatives as potential inhibitors of tubulin polymerization." Waco, Tex. : Baylor University, 2005. http://hdl.handle.net/2104/3019.
Full text
26
Marchiori, Marcelo Amorim. "Estudo estrutura-atividade da combretastina e derivados." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/277648.
Full textAbstract:
Orientadores: Douglas Soares Galvão, Scheila Furtado Braga LlanesDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin
Made available in DSpace on 2018-08-10T15:39:34Z (GMT). No. of bitstreams: 1 Marchiori_MarceloAmorim_M.pdf: 2387821 bytes, checksum: 159d3a99481a5ba6c6eb057065531e6e (MD5) Previous issue date: 2007
Resumo: A Combretastatina é um estilbeno isolado na década de 80, e vem sendo amplamente estudada pela indústria farmacêutica devido à sua promissora ação anticarcinogênica. Como fármaco anticarcinogênico, age interrompendo o ciclo de polimerização e despolimerização dos microtúbulos, componente celular extremamente importante para a motilidade, manutenção estrutural e mitose celular. Sua principal forma de atuação consiste em despolimerizar os microtúbulos estáveis das células endoteliais da vasculatura tumoral, levando ao bloqueio do fluxo sanguineo que alimenta os tumores cancerígenos. Uma das grandes vantagens da Combretastatina, em relação aos demais medicamentos antineoplásicos, é o fato de não levar à resistência medicamentosa no tratamento quimioterápico. Investigamos a estrutura da Combretastatina e 17 derivados por meio de métodos semiempíricos e estudamos a relação entre as propriedades teóricas e a atividade experimental destes compostos, utilizando três metodologias de reconhecimento de padrões: a Metodologia de Índices Eletrônicos (MIE), a Análise de Componentes Principais (PCA) e a Análise Hierárquica de Clusters (HCA). Para cada metodologia construímos regras e padrões, permitindo a classificação dos compostos em ativos e inativos, a partir das propriedades calculadas teoricamente. Os resultados das três metodologias confirmam a aplicabilidade da MIE e reforçam a importância das variáveis eletrônicas para a classificação da atividade biológica das Combretastatinas
Abstract: Combretastatin, a stilbene isolated in 80's, has been widely studied by the pharmaceutical industry due to its promising anticarcinogenic action. As an antineoplastic agent it acts interrupting the polymerization-depolymerization cycle of the microtubules, an important cellular component to motility, strutuctural maintenance and cellular mitosis. Its main feature consists in dissociate the microtubules in endothelial cells of the tumoral vascular system, leading to disruption of the blood ow that feeds the carcinomas. One of the great advantages of Combretastatin, when compared with others compounds, is the fact that it does not lead to drug resistance in chemotherapy treatments. We investigated the structure of Combretastatin and 17 derivatives using semiempirical methods. We performed the study of the relationship between theoretical properties and experimental activity of these molecules using three pattern recognition methodologies: Electronic Index Methodology (EIM), Principal Component Analysis (PCA) and Hierarchical Clusters Analysis (HCA). For each methodology we found rules and patterns capable of classifying our molecules into active or inactive, using the properties theoretically calculated. The results obtained from the three methodologies confirm the applicability of the EIM and reinforce the importance of the electronic variables for the classi cation of the biological activity of Combretastatins
Mestrado
Estrutura Eletrônica de Atomos e Moleculas
Mestre em Física
27
Polozov, Ivan V. "Interactions of class A and class L amphipathic helical peptides with model membranes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0006/NQ30110.pdf.
Full text
28
Couvineau, Pierre. "Études structure-fonction par modélisation moléculaire et mutagénèse dirigée de cibles thérapeutiques potentielles impliquées dans la régulation de l'équilibre hydrique et des fonctions cardiovasculaires." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB133/document.
Full textAbstract:
Ces travaux de thèse s'articulent autour de deux projets : les études structure-fonction de l'aminopeptidase A, d'une part, et celles du récepteur de l'apéline, d'autre part. I/ L'aminopeptidase A (APA, EC 3.4.11.7) est une aminopeptidase monozinc membranaire qui, dans le cerveau, produit l'angiotensine (Ang) III à partir de l'Ang II. L'Ang III est l'un des principaux peptides effecteurs du système rénine-angiotensine cérébral qui exerce un effet stimulateur tonique sur le contrôle central de la pression artérielle chez le rat hypertendu. Ainsi le blocage de l'APA par un inhibiteur spécifique et sélectif, l'EC33 ou sa prodrogue, le RB150, normalise la pression artérielle dans deux modèles expérimentaux d'hypertension artérielle (HTA). L'APA constitue une cible thérapeutique potentielle pour le traitement de l'HTA qui justifie le développement de nouveaux inhibiteurs de cette enzyme plus puissants et plus sélectifs que l'EC33 et avec un profil pharmacodynamique et pharmacocinétique amélioré par rapport au RB150. Pour cela, nous avons construit un modèle tridimensionnel (3D) de l'APA sur la base de la structure cristallographique de l'APA humaine récemment publiée. Nous avons ensuite validé ce modèle par des études structure-fonction par modélisation moléculaire et mutagénèse dirigée en démontrant l'implication, d'un résidu du sous-site S1 dans la spécificité de substrat acide de l'APA et de deux résidus formant le sous-site S2' interagissant avec le résidu P2' acide d'inhibiteurs tripeptidiques précédemment développés dans le laboratoire.II/ L'apéline est le ligand naturel du récepteur orphelin humain APJ (ApélineR), un récepteur à sept domaines transmembranaires couplé aux protéines G. L'apéline et son récepteur sont impliqués dans le maintien de l'équilibre hydrique et des fonctions cardiovasculaires. L'ApélineR constitue une cible thérapeutique potentielle dans le traitement de l'insuffisance cardiaque et des rétentions hydriques. Etant donné que la demi-vie de l'apéline dans la circulation sanguine est de l'ordre de la minute, l'objectif est de développer des analogues de l'apéline métaboliquement stables. Pour développer de tels composés, nous avons entrepris de comprendre comment l'apéline se lie à son récepteur et comment elle l'active. Dans ce but, nous avons construit un modèle 3D de l'ApélineR basé sur la structure cristallographique du récepteur aux chimiokines, CXCR4. Nous avons validé ce modèle par des études structure-fonction par modélisation moléculaire et mutagénèse dirigée. Nous avons identifié à la surface du récepteur, les résidus acides des boucles extracellulaires qui interagissent avec les résidus basiques de l'apéline. Nous avons ensuite développé des analogues de l'apéline-17 (K17F) métaboliquement stables par deux stratégies différentes. Premièrement, nous avons substitué chacun des résidus de l'apéline par son énantiomère de la série D ou par un acide aminé synthétique. Deuxièmement, nous avons ajouté une chaîne fluoroalkyle à l'extrémité N-terminale de l'apéline. Ces deux stratégies ont permis d'obtenir plusieurs composés dont les plus actifs sont le P92 et le LIT01-196 qui conservent des propriétés pharmacologiques identiques à celles de K17F et qui présentent une demi-vie plasmatique largement supérieure à celle du peptide endogène. Ces deux analogues se sont révélés particulièrement actifs in vivo avec une capacité à diminuer la pression artérielle et à réduire la sécrétion de vasopressine dans le sang conduisant à une augmentation de la diurèse aqueuse. Les modèles 3D validés de l'APA et de l'ApélineR seront utilisés pour des campagnes de criblage in silico de chimiothèques virtuelles afin de découvrir de nouveaux inhibiteurs de l'APA et des agonistes de l'ApélineR qui pourraient conduire à terme à de nouveaux candidats-médicaments. Ces composés pourraient être utiles pour le traitement de l'HTA et de l'insuffisance cardiaqueThe doctoral work was divided in two parts, one on the structure-function studies of aminopeptidase A, and the second one, on those of the apelin receptor. I/ Aminopeptidase A (APA) is a membrane bound monozinc aminopeptidase which generates, in the brain, angiotensin (Ang) III from Ang II. Ang III is one of the main effector peptides of the brain renin-angiotensin system, which exerts a tonic stimulatory action on the control of blood pressure in hypertensive rats. Thus, the blockade of brain APA by a specific and selective inhibitor, EC33 or its prodrug, RB150, normalizes blood pressure in two animal models of arterial hypertension (HTA). APA constitutes a potential therapeutic target for the treatment of HTA that justifies the development of more potent and selective APA inhibitors than EC33, with enhanced pharmacodynamic and pharmacokinetic profiles when compared to RB150. With this aim, we built a three dimensional (3D) model of APA based on the recently published crystal structure of human APA. We validated this model by structure-function studies combining molecular modeling and site-directed mutagenesis demonstrating the crucial role of one residue in the S1 subsite responsible for substrate specificity of APA for N-terminal acidic amino-acid residues and two other residues constituting the S2' subsite of APA involved in the binding of the P2' acidic residue of tripeptidic inhibitors, previously developed in the laboratory. II/ Apelin is the endogenous ligand of the human orphan receptor named APJ (ApelinR), a G protein-coupled receptor. Apelin and ApelinR are involved in the control of body fluid homeostasis and cardiovascular functions. ApelinR constitutes a potential therapeutic target for the treatment of heart failure and water retentions. Given that apelin half-life in the blood circulation is in the minute range, we aimed to develop potent metabolically stable apelin analogs.. In this context, it is necessary to understand how apelin binds to ApelinR and how it is activated. To do so, we build a 3D model of ApelinR based on the crystal structure of the chemokine receptor, CXCR4. We validated this model by structure-function studies by molecular modeling and site-directed mutagenesis. We showed that apelin interacts with the receptor through interactions between the basic residues of the peptide and the acidic residues of the ApelinR, located in the extracellular loops. ,We then developed metabolically stable apelin-17 (K17F) analogs following two different strategies. First, we substituted each residue of K17F by its D-isomer or a synthetic amino-acid. Secondly, we added a fluoroalkyl chain at the N-terminal part of K17F. These two strategies allowed to significantly improve plasma half-life of the modified peptides for several hours without modifying their pharmacological properties as compared to K17F. Two apelin metabolically stable analogs, P92 and LIT01-196, were found to have significantly higher in vivo activity than K17F with a strong capacity to decrease blood pressure and to inhibit vasopressin release in the blood stream inducing an increased aqueous diuresis. These new validated 3D models will be now used to perform in silico screening of virtual chemical libraries to discover new APA inhibitors and ApelinR agonists that could ultimately lead to new drug candidates. These compounds could be useful for the treatment of HTA and heart failure
29
Jover, Modrego Jesús. "Aplicació de la metodologia QSPR al càlcul de propietats de compostos inorgànics i de sistemes multicomponents." Doctoral thesis, Universitat de Barcelona, 2008. http://hdl.handle.net/10803/665934.
Full textAbstract:
En esta tesis se ha utilizado la metodología QSPR para calcular las propiedades de diferentes compuestos y sistemas complejos que no habían estudiados anteriormente. En concreto, se han establecido modelos que permiten el cálculo de la viscosidad y la tensión superficial, en estado líquido, y la entalpía de formación en fase gas para conjuntos de compuestos organometálicos de fórmula general MRnXm, en la que M puede ser un metal, semimetal o no metal de los grupos 12 al 16 de la tabla periódica; los grupos R corresponden a sustituyentes orgánicos alquílicos, arílicos, etc.; y los ligandos terminales X pueden ser cloro, bromo, yodo e hidrógeno.
Se ha estudiado también la basicidad catiónica de un conjunto de compuestos orgánicos, de naturaleza química muy diversa, frente al catión Li+. En general, esta propiedad puede asociarse a la energía del proceso de formación de los complejos [Li-Ligando]+.
Los sistemas complejos estudiados, que reciben el nombre de multicomponentes, son aquellos en los que la propiedad estudiada depende, a la vez, de dos o más elementos constituyentes del sistema. Las propiedades estudiadas en esta tesis son: las afinidades y basicidades catiónicas de los aminoácidos habituales frente a los cationes monovalentes de litio, sodio, potasio, cobre y plata; y las constantes de acidez (pKa) de familias de ácidos orgánicos en diferentes solventes, en este caso las familias de ácidos orgánicos estudiadas son fenoles, ácidos benzoicos, ácidos carboxílicos alifáticos y anilinas. En el tratamiento de estos sistemas multicomponentes se han utilizado descriptores externos para caracterizar a los cationes metálicos y los solventes. En el primer caso se han utilizado propiedades físicas, como potenciales de ionización, afinidades electrónicas, escalas de electronegatividad, etc.; para los diferentes solventes se han usado también propiedades físicas, como el momento dipolar, la constante dieléctrica, la polarizabilidad, etc.; y parámetros derivados de las diferentes escalas de polaridad más habituales, como los parámetros de Kamlet y Taft, los de Koppel y Palm, los de Drago, Gutmann, etc.
Los modelos, lineales y no lineales, desarrollados para todas las propiedades proporcionan resultados excelentes para todas ellas, con valores de R2 mayores que 0.95, errores muy bajos y capacidad predictiva elevada, comprobada mediante la utilización de conjuntos de valores externos. Además de proporcionar una manera de calcular las propiedades, los modelos establecidos contienen descriptores que permiten realizar, en todos los casos, una interpretación razonable de las propiedades en términos fisicoquímicos.
30
Onchoke, Kefa Karimu. "Experimental and theoretical studies of nitrated polycyclic aromatic hydrocarbons." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1143220534.
Full text
31
"Function/structure relationship study of trichosanthin, a Chinese medicinal protein, and its interaction with acidic ribosomal protein, PO." Thesis, 2006. http://library.cuhk.edu.hk/record=b6074107.
Full textAbstract:
Previous research showed that the C-terminal tail of TCS can be deleted to generate a mini-TCS (C7-TCS) with antigenicity. The second topic of my study is to resolve the role of the C-terminal of TCS. Structure of C7-TCS showed that deletion of the C-terminal tail destabilizes the protein structure and makes Trp192 more solvent exposed. The relationship between the C-terminal tail and Trp192 was determined by mutating Trp192 to Phe in wild-type TCS and C7-TCS, generating W192F-TCS and W192F-C7-TCS. The crystal structure of C7-TCS, [W192F]-TCS and [W192F]-C7-TCS were determined and compared. Trp192 was identified as an important residue in stabilizing the conformation of TCS. Besides, the accumulative effect of Trp192 and the C-terminal tail is significant on the ribosome-inactivating activity. By comparing the structures, it was found that, the hydrogen bond formed by amino acids 240 and 35 seems to be essential for the structure and amino acid 240 should be a critical residue for the connection of the N-terminal and C-terminal domains in trichosanthin.Ribosome-inactivating activity is the most important activity of TCS and RIPs. Therefore, the third topic of my study is to find the important of interaction between TCS and ribosomal proteins. Two ribosomal proteins, P0 and P1, have been identified previously to interact with TCS. By yeast two-hybrid screening, three cut of ten charge residues in TCS were identified to be the interaction sites between TCS and ribosomal protein P0. The interaction region was located on the surface of TCS near the entrance to the active pocket. The interaction with P0 was shown to be carried out by electrostatic interaction between the positively charge residues of TCS. However, the mutation of all the concerned residues in TCS gave only a mild reduction in inhibiting the protein synthesis of an in vitro reticulocyte translation system, showing that the interaction between TCS and P0 only plays a minor role in the ribosomal inactivating activity of TCS.
The first topic of my research is to find the role of Glu-85. The structure of [E85Q]-TCS and AMP complex was obtained. It is deduced that there are two sites for substrate binding in TCS, one is for recognition and another ion hydrolysis. The structure also indicated that protonation of substrate adenine is carried out by a water molecule in the active pocket of TCS during its N-glycosidase action.
Trichosanthin (TCS) is a Chinese medicinal protein isolated froth the root tuber of Trichosanthes kirilowi Maximowicz. It is a 27kDa protein with multiple pharmacological properties, including abortifacient, anti-tumor and anti-human immunodeficiency virus (HIV). It is believed that the pharmacological properties of TCS are related to ribosome-inactivation, by breaking, the specific glycosidic bond of adenine 4324 from the 28S rRNA.
Too Hiu Mei.
"February 2006."
Advisers: Pang-Chui Shaw; Kam-Bo Wong.
Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6213.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references (p. 164-175).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.
School code: 1307.
32
Du, Zheyuan. "Chemical Stability of Curcumin: Structure and Activity Relationship (SAR) Study." 2016. https://scholarworks.umass.edu/masters_theses_2/347.
Full textAbstract:
Over the past decades, numerous studies have shown that curcumin has potent biological activities. As a potential chemopreventing agent, curcumin was demonstrated to exert anti-cancer effects in both in vitro and in vivo studies. However, low bioavailability of curcumin limited human clinical trials and its application to be formulated as therapeutics. In this thesis, we will summarize the anti-cancer effects of curcumin in animal studies and clinical trials. In addition, an SAR study will be introduced to elucidate the mechanism of curcumin degradation at physiological pH. We synthesized various curcumin analogues and compared their stability in phosphate buffer using HPLC and colorimetry assay. The results not only demonstrated that the -OH group and the methoxy group play a critical role in stability of curcumin in physiological environment, but also support the proposed mechanism of phenolic radical formation by which curcumin degrades to its major product bicyclopentadione.
33
"Investigation of chemical shielding property and its relationship to structure of biomacromolecules using NMR and density functional theory methods." 1999. http://library.cuhk.edu.hk/record=b6073164.
Full textAbstract:
Xu, Xiao-ping."March 1999."
Thesis (Ph.D.)--Chinese University of Hong Kong, 1999.
Includes bibliographical references (p. 152-166).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Mode of access: World Wide Web.
Abstracts in English and Chinese.
34
Watts, K. Shawn. "Steps toward structure-assisted drug design." Thesis, 2000. http://hdl.handle.net/1957/32743.
Full textAbstract:
The three dimensional structure of both a ligand and its cognate receptor
are required for the success of structure-assisted drug design. This thesis reports
the crystal structure of hectochlorin, a small, bioactive molecule, and the steps
toward determining the crystal structure of an RNA molecule that is an attractive
target for drug design.
The absolute structure of hectochlorin, a cytotoxic, secondary metabolite
isolated from Lyngbya majuscula, is reported herein. Specifically, the absolute
configuration of hectochlorin, as determined by x-ray crystallography, is
reported as 6S, 7S, 10S, 31S. Marine natural products are interesting as a source
of novel chemical compounds that are potentially valuable as therapeutic agents,
or have industrial applications. The absolute structure provides a model that
serves as a starting point for rational drug design synthesis.
In a second study, results are reported from attempts to crystallize a
biologically important RNA structure, the trans-acting response element, (TAR),
for the determination of its structure by x-ray diffraction, and ultimately,
providing an initial model for structure-assisted drug design targeted against
HIV. Crystals, of biologically relevant TAR sequences, greater that 0.1 x 0.1 x 0.1
mm�� in size, both in the presence and absence of a cognate ligand analogue,
have been obtained. These crystals have been shown to be of poor diffraction
quality, but the initial crystallization conditions provide a starting point for
optimization that may yield higher quality crystals.Graduation date: 2001
35
McGoldrick, Luke Lawrence Reedy. "Structural Analyses of the Transient Receptor Potential Channels TRPV3 and TRPV6." Thesis, 2019. https://doi.org/10.7916/d8-d1x5-rw78.
Full textAbstract:
Transient receptor potential (TRP) channels comprise a superfamily of cation-selective ion channels that are largely calcium (Ca2+) permeable and that play diverse physiological roles ranging from nociception in primary afferent neurons to the absorption of dietary Ca2+. The 28 mammalian TRP channels are categorized into 6 subfamilies. The vanilloid subfamily is named for its founding member, TRPV1, the capsaicin receptor, and has 6 members. TRPV1-4 are all heat sensitive ion channels whereas TRPV5 and TRPV6 are involved in renal Ca2+ reabsorption and Ca2+ absorption in the intestine, respectively. In our structural studies, we have focused on TRPV3 and TRPV6.
TRPV6 is a highly Ca2+ selective TRP channel (PCa/PNa ~ 130) that functions in active Ca2+ absorption in the intestine. Its expression is upregulated by vitamin D and is, on the molecular level, regulated by PIP2 and calmodulin (CaM). Previously, the structure of TRPV6 was solved using X-ray crystallography. Using the crystal structure, a negatively charged extracellular vestibule was identified and anomalous diffraction was used to identify ion binding sites in the pore. Also, at the top of the selectivity filter, four aspartates were identified that coordinate Ca2+ entering the pore and confer to TRPV6 its selectivity for Ca2+. However, only the structure of the rat orthologue was solved and only in the closed, apo state. We used cryo-electron microscopy (cryo-EM) to solve structures of the human orthologue of TRPV6 in the open and closed (we used the mutation R470E to close the channel) states. The closed-to-open TRPV6 transition is accompanied by the formation of short π-helices in the middle of the pore-lining S6 helices, which in turn results in their turning and a different set of residues facing the pore. Additionally, the formation of the π-helices results in kinking of the S6 helices, which further widens the pore.
TRPV6 is constitutively active when expressed heterologously. In other words, the addition of external stimuli is not necessary for the activation of the channel. Therefore, its activity needs to be regulated to prevent toxic Ca2+ overload. One mechanism by which this occurs is through its regulation by CaM. CaM has been shown to bind TRPV6 and regulate its function, however, the way it binds to and regulates TRPV6 remained unknown. To uncover this mechanism, we solved the structure of TRPV6 bound to CaM. We found that CaM binds TRPV6 in a 1:1 stoichiometric ratio and that CaM directly blocks the TRPV6 pore by inserting a positively charged lysine into a tera-tryptophan cage at the bottom of the pore. As a result, the channel adopts an inactivated conformation; although the pore-lining S6 helices still contain local π-helices, they are pulled closer together, narrowing the pore and further blocking it with hydrophobic side chains.
We have also conducted studies of TRPV3. Unlike TRPV6, TRPV3 is a heat-activated vanilloid TRP channel. TRPV3 is expressed highly in keratinocytes where it has been implicated in wound healing and maintenance of the skin barrier, and in the regulation of hair growth. We solved the structure of apo TRPV3 in a closed state, and the structure of a TRPV3 mutant bound to 2-APB in an open state. Like TRPV6, the opening of TRPV3 is accompanied by the formation of local π-helices in the middle of the pore-lining S6 helices. The formation of the π-helices results in the lining of the ion permeation pathway with a different set of residues, resulting in a largely negatively charged pathway. Unlike TRPV6, TRPV3 is only slightly selective for Ca2+ and correspondingly, during gating state transitions, rearrangements were not only observed only in its pore-lining helices, but also in the cytosolic domain and the selectivity filter. Based on a comparison of our structures, we proposed a model of TRPV3 regulation by 2-APB.
Together, our studies provide insight into the regulatory and gating mechanisms of the vanilloid subtype TRP channels and can provide the foundation for future studies.
36
Tehan, Benjamin 1970. "Computational design of novel antipsychotics." 2003. http://arrow.monash.edu.au/hdl/1959.1/5633.
Full text
37
Parajuli, Bibek. "Identification, kinetic and structural characterization of small molecule inhibitors of aldehyde dehydrogenase 3a1 (Aldh3a1) as an adjuvant therapy for reversing cancer chemo-resistance." Thesis, 2014. http://hdl.handle.net/1805/4658.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)ALDH isoenzymes are known to impact the sensitivity of certain neoplastic cells toward cyclophosphamides and its analogs. Despite its bone marrow toxicity, cyclophos-phamide is still used to treat various recalcitrant forms of cancer. When activated, cyclo-phosphamide forms aldophosphamide that can spontaneously form the toxic phospho-ramide mustard, an alkylating agent unless detoxified by ALDH isozymes to the carbox-yphosphamide metabolite. Prior work has demonstrated that the ALDH1A1 and ALDH3A1 isoenzymes can convert aldophosphamide to carboxyphosphamide. This has also been verified by over expression and siRNA knockdown studies. Selective small molecule inhibitors for these ALDH isoenzymes are not currently available. We hypothe-sized that novel and selective small molecule inhibitors of ALDH3A1 would enhance cancer cells’ sensitivity toward cyclophosphamide. If successful, this approach can widen the therapeutic treatment window for cyclophosphamides; permitting lower effective dos-ing regimens with reduced toxicity. An esterase based absorbance assay was optimized in a high throughput setting and 101, 000 compounds were screened and two new selective inhibitors for ALDH3A1, which have IC50 values of 0.2 µM (CB7) and 16 µM (CB29) were discovered. These two compounds compete for aldehyde binding, which was vali-dated both by kinetic and crystallographic studies. Structure activity relationship dataset has helped us determine the basis of potency and selectivity of these compounds towards ALDH3A1 activity. Our data is further supported by mafosfamide (an analog of cyclo-phosphamide) chemosensitivity data, performed on lung adenocarcinoma (A549) and gli-oblastoma (SF767) cell lines. Overall, I have identified two compounds, which inhibit ALDH3A1’s dehydrogenase activity selectively and increases sensitization of ALDH3A1 positive cells to aldophosphamide and its analogs. This may have the potential in improving chemotherapeutic efficacy of cyclophosphamide as well as to help us understand better the role of ALDH3A1 in cells. Future work will focus on testing these compounds on other cancer cell lines that involve ALDH3A1 expression as a mode of chemoresistance.