Дисертації з теми "Biomolecular and medicinal chemistry"
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Mantri, Yogita. "Computational modeling of transition metals in medicinal chemistry realistic models to probe metal-biomolecule binding energetics /." [Bloomington, Ind.] : Indiana University, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3386701.
Повний текст джерелаTitle from PDF t.p. (viewed on Jul 22, 2010). Source: Dissertation Abstracts International, Volume: 70-12, Section: B, page: 7549. Adviser: Mu-Hyun Baik.
Frischkorn, Kate E. "Preparation of Supramolecular Amphiphilic Cyclodextrin Bilayer Vesicles for Pharmaceutical Applications." DigitalCommons@CalPoly, 2018. https://digitalcommons.calpoly.edu/theses/1894.
Повний текст джерелаShenton, Wayne. "Biomolecular approaches to nanophase chemistry." Thesis, University of Bath, 1998. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300767.
Повний текст джерелаCheviet, Thomas. "Ciblage d'enzymes du métabolisme purique chez Plasmodium falciparum : Conception et étude de molécules bioactives." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTS121.
Повний текст джерелаMalaria, a global public health problem, is due to several parasites which are characterized by presenting only one nucleotide biosynthesis pathway : the recovery path. As part of a rational design of inhibitors of enzymes involved in purine cycle of Plasmodium Flaciparum (one of parasites responsible for malaria), several compounds have shown promising results. This PhD project will focus firstly on the structural optimization of these hits, in interaction with a team of biologists (SAR) and of structuralists (structure-fonction-activity relationship), and secundly on the development of LC/MS/MS dosage methods to identify and study the biological targets, and reveal the impact of the omptimized compounds on the purine metabolism
Rajarathinam, Kayathri. "Nutraceuticals based computational medicinal chemistry." Licentiate thesis, KTH, Teoretisk kemi och biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-122681.
Повний текст джерелаQC 20130531
Wang, Nuo. "Computational Studies on Biomolecular Diffusion and Electrostatics." Thesis, University of California, San Diego, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3731932.
Повний текст джерелаAs human understandings of physics, chemistry and biology converge and the development of computers proceeds, computational chemistry or computational biophysics has become a substantial field of research. It serves to explore the fundamentals of life and also has extended applications in the field of medicine. Among the many aspects of computational chemistry, this Ph. D. work focuses on the numerical methods for studying diffusion and electrostatics of biomolecules at the nanoscale. Diffusion and electrostatics are two independent subjects in terms of their physics, but closely related in applications. In living cells, the mechanism of diffusion powers a ligand to move towards its binding target. And electrostatic forces between the ligand and the target or the ligand and the environment guide the direction of the diffusion, the correct binding orientation and, together with other molecular forces, ensure the stability of the bound complex. More abstractly, diffusion describes the stochastic manner biomolecules move on their energy landscape and electrostatic forces are a major contributor to the shape of the energy landscape. This Ph. D. work aims to acquire a good understanding of both biomolecular diffusion and electrostatics and how the two are used together in numerical calculations. Three projects are presented. The first project is a proof of concept of the bead-model approach to calculate the diffusion tensor. The second project is the benchmark for a new electrostatics method, the size-modified Poisson-Boltzmann equation. The third project is an application that combines diffusion and electrostatics to calculate the substrate channeling efficiency between the human thymidylate synthase and dihydrofolate reductase.
Pittock, Chris. "Using linear-scaling DFT for biomolecular simulations." Thesis, University of Southampton, 2014. https://eprints.soton.ac.uk/362968/.
Повний текст джерелаShi, Dong-Fang. "The medicinal chemistry of antitumour benzazoles." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283645.
Повний текст джерелаBrown, Stacy D., Andy Coop, Paul Trippier, and Eric Walters. "Contemporary Approaches For Teaching Medicinal Chemistry." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/5251.
Повний текст джерелаAniagyei, Stella Emefa. "Studies of nanoparticles as probes for nucleation and biomolecular self-assembly." [Bloomington, Ind.] : Indiana University, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3386662.
Повний текст джерелаTitle from PDF t.p. (viewed on Jul 20, 2010). Source: Dissertation Abstracts International, Volume: 70-12, Section: B, page: 7527. Adviser: Bogdan Dragnea.
Kim, Meekyum Olivia. "Integrating conformational and protonation equilibria in biomolecular modeling." Thesis, University of California, San Diego, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3709257.
Повний текст джерелаDue to high sensitivity of biomolecular systems to the electrostatic environments, coupled treatment of conformational and protonation equilibria is required for an accurate characterization of true ensemble of a given system. The research presented in this dissertation examines the effects of conformational and protonation equilibria of varying extent on diverse aspects of computational biomolecular modeling, as introduced in Chapter 1. The effects of protonation and stereoisomerism of two histidines on virtual screening against the M. tuberculosis enzyme RmlC are presented in Chapter 2. In Chapter 3, conformational flexibility of three M. tuberculosis prenyl synthases is probed using molecular dynamics simulations, with implications for computer-aided drug discovery effort for the new generation antibacterial and antivirulence therapeutics. Chapters 4 and 5 consider the conformational and protonation equilibria simultaneously by utilizing constant pH molecular dynamics, in which fluctuations in both conformation and protonation state are possible. In Chapter 4, a computational protocol utilizing constant pH molecular dynamics to compute pH-dependent binding free energies is presented. The methodology is further applied to protein-ligand complexes in Chapter 5, where the thermodynamic linkage between protonation equilibria, conformational dynamics, and inhibitor binding is illustrated.
Rienstra, Chad M. "Solid state nuclear magnetic resonance methodology for biomolecular structure determination." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/9524.
Повний текст джерелаIncludes bibliographical references.
Several developments in solid state nuclear magnetic resonance (SSNMR) spectroscopy methods are presented. All studies are performed with magic angle spinning (MAS) and high-power proton decoupling, for optimal sensitivity and resolution. Chemical shift are assigned by multi-dimensional correlation spectroscopy in isotopically enriched molecules ...
by Chad Michael Rienstra.
Ph.D.
Elfwing, Anders. "On decoration of biomolecular scaffolds with a conjugated polyelectrolyte." Doctoral thesis, Linköpings universitet, Biomolekylär och Organisk Elektronik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-141675.
Повний текст джерелаAkay, Senol. "Diagnosis and Inhibition Tools in Medicinal Chemistry." Digital Archive @ GSU, 2009. http://digitalarchive.gsu.edu/chemistry_diss/41.
Повний текст джерелаBrown, Stacy D. "Using Guided Inquiry to Teach Medicinal Chemistry." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/5249.
Повний текст джерелаÖster, Carl. "Investigating interactions using solid state NMR : applications to biomolecular complexes." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/99641/.
Повний текст джерелаSanchez-Cano, Carlos. "Biomolecular interactions and cellular effects of steroidal and metallosupramolecular metallodrugs." Thesis, University of Birmingham, 2009. http://etheses.bham.ac.uk//id/eprint/494/.
Повний текст джерелаBarnes, Alexander B. (Alexander Benjamin). "High-resolution high-frequency dynamic nuclear polarization for biomolecular solid state NMR." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/65263.
Повний текст джерелаVita. Cataloged from PDF version of thesis.
Includes bibliographical references.
Dynamic Nuclear Polarization (DNP) has exploded in popularity over the last few years, finally realizing its potential to overcome the detrimental lack of sensitivity that has plagued performing NMR experiments. Applied to magic angle spinning (MAS) experiments, this renaissance of DNP has been primarily driven by the development of instrumentation; namely gyrotron oscillators as high-power stable microwave power sources and the NMR probes and associated equipment required to spin samples routinely below 100 Kelvin. The first three chapters of this thesis provide an overview of the theory, instrumentation, and applications of DNP. Chapter 1 introduces the magnetic resonance Hamiltonian with a focus on interactions that are necessary to control in order to obtain high-resolution DNP spectra. Chapters 2 and 3 are published reviews of DNP. Whereas Chapter 2 targets magnetic resonance spectroscopists, Chapter 3 is intended for an electric engineering audience. Both reviews are included as the associated depth and coverage of the topics are complementary and lead to a better understanding of DNP. The later chapters describe in detail advancements in probe, cryogenics, and gyrotron technology required to perform DNP MAS experiments, as well as the gains in sensitivity and resolution such instrumentation has permitted. Of particular importance is the development of a cryogenic sample ejection system that resulted in exquisite resolution of spectra recorded <100 K, both of crystalline peptide and the active site of membrane proteins. Such developments in instrumentation and demonstrations of resolution go towards overturning a long-held stance in the field that DNP would always suffer from broadened, unresolved spectra. Such techniques also allow us to investigate site specific dynamics of a crystalline peptide, the high resolution SSNMR structure of which is discussed in Chapter 3. DNP and the developed instrumentation is also leveraged to measure inter-atomic distances in the active site of a membrane protein with sub-angstrom precision. Chapters 7 describes the calculation of the microwave field strength across the sample in a MAS DNP probe and introduces strategies to increase it. Finally Chapter 8 introduces a major advance in the microwave source technology associated with DNP experiments. Detailed designs of a novel 250 GHz gyrotron oscillator are shown and experiments demonstrate a continuous broad 3 GHz bandwidth with >10 W across the band, which results in substantially improved DNP performance.
by Alexander B. Barnes.
Ph.D.
Lunga, Mayibongwe J. "A medicinal chemistry study in nitrogen containing heterocycles." Thesis, Rhodes University, 2018. http://hdl.handle.net/10962/63521.
Повний текст джерелаElboray, Elghareeb Elshahat Elghareeb. "Catalytic cascades creating novel architecture for medicinal chemistry." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/8036/.
Повний текст джерелаLi, Ju-Yun. "Quantitative structure-activity relationship studies in medicinal chemistry." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062596938.
Повний текст джерелаRigby-Singleton, Shellie. "Scanning probe and optical tweezer investigations of biomolecular interactions." Thesis, University of Nottingham, 2003. http://eprints.nottingham.ac.uk/10001/.
Повний текст джерелаWaghela, M. B. "Pyrrolizine derivatives of potential medicinal interest." Thesis, De Montfort University, 1986. http://hdl.handle.net/2086/13287.
Повний текст джерелаNjaria, Paul Magutu. "Antimycobacterial 2-aminoquinazolinones and benzoxazole-based oximes: synthesis, biological evaluation, physicochemical profiling and supramolecular derivatization." Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/26954.
Повний текст джерелаJanczak, Colleen. "Hybrid Nanoparticles for Enhanced Sensitivity in Biological Labeling and Biomolecular Sensing." Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/202514.
Повний текст джерелаVanMetre, Holly Sue Morris. "Individual submicrometer particles and biomolecular systems studied on the nanoscale." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3207.
Повний текст джерелаBennett, Matthew Stuart. "Crystallography of biomolecular complexes, revealing protein-nucleoside, protein-protein acid-drug interactions." Thesis, King's College London (University of London), 2002. https://kclpure.kcl.ac.uk/portal/en/theses/crystallography-of-biomolecular-complexes-revealing-proteinnucleoside-proteinprotein-aciddrug-interactions(4a85b5cd-8a9a-4969-bee3-95fbe46e4257).html.
Повний текст джерелаChen, Dianne Tzu-Hsiu. "Phytochemical studies on traditional medicinal plants with antimalarial activities." Master's thesis, University of Cape Town, 1997. http://hdl.handle.net/11427/21853.
Повний текст джерелаLlano, Jorge. "Modern Computational Physical Chemistry : An Introduction to Biomolecular Radiation Damage and Phototoxicity." Doctoral thesis, Uppsala University, Department of Cell and Molecular Biology, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4224.
Повний текст джерелаThe realm of molecular physical chemistry ranges from the structure of matter and the fundamental atomic and molecular interactions to the macroscopic properties and processes arising from the average microscopic behaviour.
Herein, the conventional electrodic problem is recast into the simpler molecular problem of finding the electrochemical, real chemical, and chemical potentials of the species involved in redox half-reactions. This molecular approach is followed to define the three types of absolute chemical potentials of species in solution and to estimate their standard values. This is achieved by applying the scaling laws of statistical mechanics to the collective behaviour of atoms and molecules, whose motion, interactions, and properties are described by first principles quantum chemistry. For atomic and molecular species, calculation of these quantities is within the computational implementations of wave function, density functional, and self-consistent reaction field theories. Since electrons and nuclei are the elementary particles in the realm of chemistry, an internally consistent set of absolute standard values within chemical accuracy is supplied for all three chemical potentials of electrons and protons in aqueous solution. As a result, problems in referencing chemical data are circumvented, and a uniform thermochemical treatment of electron, proton, and proton-coupled electron transfer reactions in solution is enabled.
The formalism is applied to the primary and secondary radiation damage to DNA bases, e.g., absorption of UV light to yield electronically excited states, formation of radical ions, and transformation of nucleobases into mutagenic lesions as OH radical adducts and 8-oxoguanine. Based on serine phosphate as a model compound, some insight into the direct DNA strand break mechanism is given.
Psoralens, also called furocoumarins, are a family of sensitizers exhibiting cytostatic and photodynamic actions, and hence, they are used in photochemotherapy. Molecular design of more efficient photosensitizers can contribute to enhance the photophysical and photochemical properties of psoralens and to reduce the phototoxic reactions. The mechanisms of photosensitization of furocoumarins connected to their dark toxicity are examined quantum chemically.
Ni, Nanting. "Application of Boronic Acids in Medicinal Chemistry (Inhibitors, Sensors)." Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/chemistry_diss/34.
Повний текст джерелаBaxter-Jones, C. S. "Some aspects of the medicinal chemistry of immunomodulatory compounds." Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235379.
Повний текст джерелаFoster, R. W. "Sustainable approaches to novel heterocyclic scaffolds for medicinal chemistry." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1470876/.
Повний текст джерелаSherer, Christopher. "A multidisciplinary investigation into the design, synthesis and evaluation of a novel class of anti-glioblastoma drug fragments." Thesis, University of Central Lancashire, 2017. http://clok.uclan.ac.uk/20462/.
Повний текст джерелаDiScipio, Regina. "Light, Matter, Action: Electronic Relaxation Processes in Biomolecular Photosensitizers and in Photovoltaics." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1522958286743542.
Повний текст джерелаSherman, B. Woody (Brian Woody) 1977. "Biomolecular ligand design : enhancing binding affinity and specificity utilizing electrostatic charge optimization and packing techniques." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/17740.
Повний текст джерелаVita.
Includes bibliographical references (p. 257-281).
Theory and methods to design ligands with enhanced binding affinity and specificity for use as biological therapeutics were developed. These methods involve electrostatic charge optimization techniques and packing considerations. First, a detailed investigation of a transition state analog (TSA) binding to the E. coli chorismate mutase enzyme was performed. This study included an electrostatic component analysis of both the ligand and receptor to understands the determinants of binding as well as an optimization of the TSA charges that revealed that the system was well optimized for binding. In another study, a method was developed to predict potential affinity-enhancing modifications to a protein therapeutic. An antibody raised against the VLA-1 [alpha]-1 [beta]-1 integrin was used in this study and several mutation predictions arose that were computed to enhance binding affinity to the target. The set of predictions could be classified into four groups based on their physical characteristics within the system. The residues making long range electrostatic interactions were found to have the highest percentage of computed affinity-enhanced binders. Finally, an extension to the affinity charge optimization theory was implemented that accounted for broad and narrow specificity of binding. An application to the protease of HIV was performed to explore the determinants of specificity. General principles were found in a narrow specificity study with HIV protease as a target and the human aspartyl proteases pepsin and cathepsin D as decoys that may help to elucidate principles for designing more selective inhibitors.
(cont. ) In a broad specificity study with wild type HIV protease and several escape mutant proteases, we found common features on the protease that could be targeted to create a new generation of HIV protease inhibitors that are not as susceptible to viral resistance as the current therapeutics.
by B. Woody Sherman.
Ph.D.
Orrling, Kristina M. "On the Versatility of Microwave-Assisted Chemistry : Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-101356.
Повний текст джерелаBajaj, Vikram Singh. "Dynamic nuclear polarization in biomolecular solid state NMR : methods and applications in peptides and membrane proteins." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/40874.
Повний текст джерелаIncludes bibliographical references.
Solid state NMR can probe structure and dynamics on length scales from the atomic to the supramolecular. However, low sensitivity limits its application in macromolecules. NMR sensitivity can be improved by dynamic nuclear polarization (DNP), in which electron polarization is transferred to nuclei. We present applications of magic angle spinning NMR that demonstrate its utility for the determination of structure at atomic resolution. We then present new techniques and instrumentation for DNP that permit these methods to be applied to larger systems such as membrane proteins. These applications rest on several advances in instrumentation: millimeter-wave sources and conduits of power to the sample; low-temperature MAS probes incorporating millimeter-wave transmission; cryogenics and pneumatic control systems. We describe a 380 MHz DNP spectrometer incorporating a 250 GHz gyrotron oscillator and present the theory and operation of a 460 GHz gyrotron at the second harmonic of electron cyclotron resonance. We have applied DNP to study trapped photo cycle intermediates of the archael membrane protein bacteriorhodopsin, a light-driven transmembrane ion pump.
(cont.) We have observed the K photointermediate for the first time by NMR and found unexpected conformational heterogeneity in the L intermediate. With multidimensional correlation spectroscopy, we have assigned active site resonances in conformational mixtures of photointermediates of [U-13C,'SN]-bR with high sensitivity. By using non-linear sampling of indirect dimensions, we have observed transient product of K accumulation. We present frequency-selective experiments for amino acid-selective assignments and the measurement of heteronuclear distances and torsion angles in [U-13C, N]-bR and discuss the relevance of these results to its photocycle. In addition, we describe several applications of solid state NMR, including a study of dynamic and structural phase transitions in peptides and proteins near the canonical glass transition temperature. We present resonance width experiments that can be used to measure homonuclear and heteronuclear dipolar couplings in uniformly labeled solids.
(cont.) Finally, we discuss applications to amyloid fibrils, which are protein aggregates that are implicated in diseases of protein misfolding. We report the atomic resolution structure of the disease-associated L 111M mutant of TTR105-115 in an amyloid fibril, and information about the supramolecular structure of fibrils from WT TTRos05115.
by Vikram Singh Bajaj.
Ph.D.
Thompson, Meghan L. "Physicochemical and Structural Analysis of Polymers as Putative Drugs." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4061.
Повний текст джерелаSchwehm, Carolin Maria. "Synthesis of 3-dimensional scaffolds for application in medicinal chemistry." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/32362/.
Повний текст джерелаLima, Barbosa Ana Soraya. "Organometallic compounds of tin and ruthenium : applications in medicinal chemistry." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAF029.
Повний текст джерелаRelated to antimicrobial research, we synthesized tin compounds derived from undecylenic, ricinoleic and caprylic acids and we found that they show very high activity against some strains of bacteria and yeast, even in nM range, being up to four thousand times more potent against Staphylococcus aureus than against mammalian cells. For ruthenium compounds, in turn, we have confirmed that the mode of action of some compounds that were synthesized recently is undoubtedly different from Cisplatin or other ruthenium compounds, because of their high stability toward substitution reactions. Finally, during the vectorization of compounds derived from Ru with Affitin we have gained important knowledge about a possible mechanism of action of this type of molecule: it could indeed be possible that these compounds which have a very reduced redox potential compared to corresponding compounds can cause polymerization of proteins by electron transfer
Di, Martino Giovanni Paolo <1985>. "Computational Methods in Biophysics and Medicinal Chemistry: Applications and Challenges." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6329/.
Повний текст джерелаHolloway, C. M. "Aspects of the medicinal chemistry associated with the ergopeptide alkaloids." Thesis, University of Nottingham, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373332.
Повний текст джерела(8782670), Joseph D. Bungard. "Design and Synthesis of HIV-1 Protease Inhibitors Featuring a Bicyclic Hexahydropyrrolofuran Scaffold." Thesis, 2020.
Знайти повний текст джерелаSince 1981, HIV/AIDS has affected over 70 million individuals worldwide. Due to the incorporation of Combination Antiretroviral Therapy (cART), this deadly virus has now become a manageable chronic illness with a reduction in mortality and morbidity rates. Combination therapy targets multiple stages of the HIV replication cycle including fusion, entry, reverse transcription, integration, and maturation. The HIV-1 protease enzyme is responsible for cleavage and processing of viral polyproteins into mature enzymes and is a common therapeutic target for inhibition of HIV. To date, there have been many protease inhibitors approved by the FDA and introduced into the market. However, mutations within the protease enzyme has rendered some of these inhibitors ineffective. This has led to an ever-growing need to develop novel protease inhibitors to combat drug resistance through mutations. Described herein is the design, synthesis, and biological evaluation of HIV-1 protease inhibitors featuring a novel hexahydropyrrolofuran (HPF) bicyclic scaffold as a P2 ligand to target binding interactions with Asp29 and Asp30. The HPF ligand provides a molecular handle that allows for further structure-activity discoveries within the enzyme. The HIV-1 protease inhibitors discussed feature carbamate, carboxamide, and sulfonamide derivatives which displayed good to excellent activity.
(6624113), Mingding Wang. "TARGETED DELIVERY OF DASATINIB FOR ACCELERATED BONE FRACTURE REPAIR." Thesis, 2020.
Знайти повний текст джерелаApproximately 6.3 million bone fractures occur annually in the USA, resulting in considerable morbidity, deterioration in quality of life, loss of productivity and wages, and sometimes death (e.g. hip fractures). Although anabolic and antiresorptive agents have been introduced for treatment of osteoporosis, no systemically-administered drug has been developed to accelerate the fracture healing process. To address this need, we have undertaken to target a bone anabolic agent selectively to fracture surfaces in order to concentrate the drug’s healing power directly on the fracture site. We report here that conjugation of dasatinib to a bone fracture-homing oligopeptide via a releasable linker reduces fractured femur healing times in mice by ~60% without causing overt off-target toxicity or remodeling of nontraumatized bones. Thus, achievement of healthy bone density, normal bone volume, and healthy bone mechanical properties at the fracture site is realized after only 3-4 weeks in dasatinib-targeted mice, but requires ~8 weeks in PBS-treated controls. Moreover, optimizations have been implemented to the dosing regimen and releasing mechanisms of this targeted-dasatinib therapy, which has enabled us to cut the total doses by half, reduce the risk of premature release in circulation, and still improve upon the therapeutic efficacy. These efforts might reduce the burden associated with frequent doses on patients with broken bones and lower potential toxicity brought by drug degradation in the blood stream. In addition to dasatinib, a few other small molecules have also been targeted to fracture surfaces and identified as prospective therapeutic agents for the acceleration of fracture repair. In conclusion, in this dissertation, we have successfully targeted dasatinib to bone fracture surfaces, which can significantly accelerate the healing process at dasatinib concentrations that are known to be safe in oncological applications. A modular synthetic method has also been developed to allow for easy conversion of a bone-anabolic warhead into a fracture-targeted version for improved fracture repair.
(6859052), Jacqueline N. Williams. "DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF POTENT HIV-1 PROTEASE INHIBITORS WITH NOVEL BICYCLIC OXAZOLIDINONE AND BIS SQUARAMIDE SCAFFOLDS." Thesis, 2019.
Знайти повний текст джерелаIn 2018, the World Health Organization (WHO) reported approximately 37 million people are living with the Human Immunodeficiency Virus (HIV). Suppressing replication of the virus down to undetectable levels was achieved by combination antiretroviral therapy (cART) which effectively reduced the mortality and morbidity rates of HIV positive individuals. Despite the improvements towards combatting HIV/AIDS, no successful treatment exists to eradicate the virus from an infected individual. Treatment regimens are lifelong and prompt less than desirable side effects including but not limited to; drug-drug interactions, toxicity, systemic organ complications, central nervous system HIV triggered disorders and most importantly, drug resistance. Current therapies are becoming ineffective against highly resistant HIV strains making the ability to treat long-term viral suppression a growing issue. Therefore, potent and more effective HIV inhibitors provide the best chance for long-term successful cART.
HIV-1 protease (PR) enzyme plays a critical role in the life cycle and replication of HIV. Significant advancements were achieved through structure-based design and X-ray crystallographic analysis of protease-bound to HIV-1 and brought about several FDA protease inhibitors (PI). Highly mutated HIV-1 variants create a challenge for current and future treatment regimens. This thesis work focuses on the design, synthesis, and evaluation of two new classes of potent HIV-1 PIs that exhibit a novel bicyclic oxazolidinone feature as the P2 ligand and a novel bis squaramide scaffold as the P2/P3 ligand. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Inhibitors 1.65g and 1.65h were further evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants and displayed antiviral activity similar to Darunavir. X-ray crystal structures of inhibitor 1.65a and inhibitor 1.65i were co-crystallized with wild type HIV-1 protease and solved at a 1.22 Å and 1.30 Å resolution and maintained strong hydrogen bond with the backbone of the PR enzyme.
(5930654), Lisha Ha. "EVALUATION OF STAPHYLOCOCCUS AURUES RNPA PROTEIN AS AN ANTIBACTERIAL TARGET." Thesis, 2019.
Знайти повний текст джерелаStaphylococcus aureus (S. aureus) is a Gram-positive pathogen that causes a wide range of infections in both hospitals and communities, of which the total mortality rate is higher than AIDS, tuberculosis, and viral hepatitis combined. The drug resistant S. aureus is a member of the “ESKAPE” pathogens that require immediate and sustained actions of novel method to combat. However, the current antimicrobial development against S. aureus is in stagnation, which underscores the urgent need for novel antimicrobial scaffolds and targets. S. aureus Ribonuclease P protein (RnpA) is an essential protein that plays important roles in both tRNA maturation and mRNA degradation pathways. The goal of this research was to evaluate RnpA as an antimicrobial target using biophysical methods. The crystal structures of wild-type RnpA in three different constructs were determined, among which the tag-free RnpA construct has a structural model of 2.0 Å resolution and Rcrys/Rfree= 0.214/0.234, and its crystals are reproducible. This crystal structure of tag-free S. aureus RnpA shows a globular representation with key structural motifs, including the “RNR” Ribonuclease P RNA binding region and a substrate binding central cleft, which shares high similarity to previously solved RnpA structures from other species despite of their low sequence identity. Meanwhile, in a screen of S. aureus RnpA mutants performed by our collaborator, RnpAP89A was found lacking the mRNA degradation activity while retaining the tRNA maturation function, and causing defects in cell viability. We therefore studied this mutant using differential scanning fluorimetry, crystallography, and circular dichroism. It was shown that RnpAP89A is thermally less stable than wild-type RnpA by ~2.0 ˚C, but no secondary structural or 3D conformational differences were found between the two proteins. Although the mutant RnpAP89A requires further characterization, the results of the studies in this thesis have begun to shed light on the relatively new role of S. aureus RnpA in mRNA degradation, and will serve as useful tools in future structure-based drug discovery for multi-drug resistant S. aureus treatment.
(5929982), Aaron R. Lindstrom. "Synthesis and Identification of Novel Arylnaphthalene V-ATPase Inhibitors as Selective Anti-Filoviral Agents." Thesis, 2020.
Знайти повний текст джерела(6616715), Kwaku Kyei-Baffour. "DEVELOPMENT OF ARYL ISONITRILES AS ANTIMICROBIAL AGENTS, AND TOTAL SYNTHESIS OF 17-NOR-EXCELSINIDINE." Thesis, 2019.
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Infectious diseases caused by bacteria, fungi, and plasmodium parasites are a huge global health problem which ultimately leads to millions of deaths annually. The emergence of strains that exhibit resistance to nearly every class of antimicrobial agents, and the inability to keep up with these resistance trends has brought to the fore the need for new therapeutic agents (antibacterial, antifungal, and antimalarial) with novel scaffolds and functionalities capable of targeting microbial resistance. A novel class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically relevant strains of methicillin-resistant Staphylococcus aureus (MRSA). Synthesis, structure-activity relationship (SAR) studies, and biological investigations have led to lead molecules that exhibit anti-MRSA inhibitory activity as low as 1 – 2 µM. The most potent compounds have also been shown to have low toxicity against mammalian cells and exhibit in vivo efficacy in MRSA skin and thigh infection mouse models.
The novel aryl isonitriles have also been evaluated for antifungal activity. This study examines the SAR of aryl isonitrile compounds and showed the isonitriles as compounds that exhibit broad spectrum antifungal activity against species of Candida and Cryptococcus. The most potent derivatives are capable of inhibiting growth of these pathogens at concentrations as low as 0.5 µM. Notably, the most active compounds exhibit excellent safety profile and are non-toxic to mammalian cells up to 256 µM.
Beyond the antibacterial and antifungal activities, structure-antimalarial relationship analysis of over 40 novel aryl isonitrile compounds has established the importance of the isonitrile functionality as an important moiety for antimalarial activity. Of the many isonitrile compounds exhibiting potent antimalarial activity, two have emerged as leads with activity comparable to that of Artemisinin. The SAR details presented in this study will prove essential for the development new aryl isonitrile analogues to advance them to the next step in the antimalarial drug discovery process.
17-nor-Excelsinidine, a zwitterion monoterpene indole alkaloid isolated from Alstonia scholaris is a subject of synthetic scrutiny. This is primarily due to its intriguing chemical structure which includes a bridged bicyclic ammonium moiety, and its anti-adenovirus and anti-HSV activity. Herein we describe a six-step total synthesis of (±)-17-nor-Excelsinidine from tryptamine. Key to the success of this synthesis is the use of palladium-catalyzed carbonylative heck lactamization methodology which built the 6, 7-membered ring lactam in one step. The resulting pentacyclic product, beyond facilitating the easy access to (±)-17-nor-Excelsinidine, could also serve as a precursor to other related indole alkaloids.
(11250960), Guangping Dong. "PRODUCT SPECIFICITY AND INHIBITION OF PROTEIN N-TERMINAL METHYLTRANSFERASE 1/2." Thesis, 2021.
Знайти повний текст джерела(11205204), Spencer D. Lindeman. "DESIGN, SYNTHESIS, AND PRECLINICAL EVALUATION OF LIGAND-TARGETED CONJUGATES FOR CANCER RADIOTHERANOSTICS." Thesis, 2021.
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