Dissertations / Theses on the topic 'Molecular design'
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1
Hodgkin, E. E. "Molecular similarity in computer-aided molecular design." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379971.
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Small, Lara Siobhan Rebecca. "Peptide-based molecular motor design." Thesis, Durham University, 2015. http://etheses.dur.ac.uk/11408/.
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This thesis concerns the use of dimeric coiled-coil peptides as components for synthetic protein motors. Studies of the hub structures of two motor designs are described. Firstly, I discuss experiments on the interactions between peptides designed for use in the Tumbleweed hub, a three-legged motor design containing three dimeric coiled-coil domains. Biophysical characterisation is carried out, including experiments to test the specificity of the interactions, which enable the peptides to be successful potential components for a stable hub structure. Secondly, I discuss the design of another motor hub, with two coiled-coil domains, using similar peptides to those used in the Tumbleweed system. The requirements for this design to produce a progressive motor are discussed. The design requires one peptide spanning the length of the motor hub, which has residues involved in both coiled-coil domains. These two coiled coil-contributing regions are linked by a central span of residues. Inducing a conformational change in this central region, in order to change the dimensions of the hub, is investigated, with the introduction of an azobenzene moiety in its cis and trans isomeric forms, using MD simulations. The ability of various residues to affect the range of conformational states this central region occupies is also investigated. Experimental studies of one of the possible systems are outlined and analysed.
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Branton, Philip Michael. "Molecular design of inorganic materials." Thesis, University of Surrey, 1998. http://epubs.surrey.ac.uk/844618/.
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Work on modelling compounds possessing die tetraaza[14]annulene (TAA) fragment is described. Modelling studies have been conducted to investigate both structural and electronic properties, of both single molecules and extended arrays of these compounds. The structural aspects have been investigated using molecular mechanics and crystallographic database investigations. Molecules based on the tetraaza[14] annulene structure have been found to adopt one of four conformations. The geometries of these conformations are planar, saddle-shaped, slightly twisted, and dome-shaped. The complexed metal centre and the arrangement of substituents on the periphery of the ligand, have been found to determine which conformation a molecule adopts. In order to model the compounds, three new atom types have been created for the Universal Force Field. The electronic aspects have been investigated using Hartree Fock based calculations for single molecules and Extended Huckel based calculations for extended systems. The electronics of die single molecules have shown there to be a linear trend in the LUMO energies, although die HOMO energies vary very little. The reason for this trend in the LUMOs is unknown, but appears not to be related to any obvious structural feature.
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Chow, Brian 1978. "The design of a molecular assembly line based on biological molecules." Thesis, Massachusetts Institute of Technology, 2003. http://hdl.handle.net/1721.1/61137.
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Thesis (S.M.)--Massachusetts Institute of Technology, School of Architecture and Planning, Program in Media Arts and Sciences, 2003.Includes bibliographical references (leaves 78-83).
A general scheme towards a "molecular assembly line" based on biological molecules is proposed, as well as its potential uses as a universal polymer scaffold in programmed assembly and molecular electronics. It is based on the principles of the biological molecules polyketide synthase and kinesin, and in some embodiments, may employ biomolecules like DNA as components of the system. The scheme entails the construction of a polymeric chain that moves a shuttle along the chain by controlling the interactions between the shuttle and individual monomer units using external inputs. The experimental work here particularly focuses on the design and synthesis of the monomer units and shuttles, as well as the mechanisms of control over the monomer/shuttle interactions that are required to construct the proposed polymer systems. Two approaches are explored, the first of which utilizes radio-frequency magnetic fields to selectively dehybridize DNA by coupling RF to covalently attached nanoparticle antennae. The second approach utilizes wavelength selective photocleavage of carbonyl bonds to control the equilibrium of a Michael reaction, and will demonstrate how one can construct a purely synthetic analogue of a polyketide synthase.
by Brian Chow.
S.M.
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Inverarity, Iain Andrew. "Marked small molecule libraries : a new approach to molecular probe design." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/14147.
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This thesis documents a new approach for the identification of a small biologically active molecule’s site of interaction, through the rapid synthesis of molecular probes. A marked library approach has been developed whereby a biocompatible marker is attached onto the small molecule’s molecular scaffold. This marker plays no role in the screening process itself, but facilitates the formation of a range of molecular probes from active marked library members. As an example of molecular probe formation, site selective biotinylation will be discussed in the introduction. This marked library concept has been applied to the natural product anisomycin A. Investigations focused on development of a detailed structure activity relationship for anisomycin’s activation of the stress activated protein kinase (SAPK) pathway, along with the synthesis of a number of marked library analogues. The active marked library members were then converted to a range of functional molecular probes utilising the copper(I) catalysed Huisgen cycloaddition as the key coupling step. These molecular probes are being used in the elucidation of anisomycin’s biological target for activation of the SAPK pathway. In a further demonstration of this strategy, a focused library of marked steroids has been synthesised based on the functionalisation of dehydroepiandrosterone B. Directed by the results of preliminary biological screening, a number of marked library members have been converted into fluorescent molecular probes. These probes will be used in future applications to probe the biological action of the dehydroepiandrosterone.
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Atalar, Taner. "Molecular Design Of Some Potential Explosives." Phd thesis, METU, 2009. http://etd.lib.metu.edu.tr/upload/3/12610318/index.pdf.
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With existing energetic materials, the on going demand from the user for increased performance with reduced vulnerability induces the synthesis of novel explosives. The need to control costs ensured that theoretical methods can help to eliminate any poor candidates due to performance and safety problems. Thus, this study is aimed to design of some potential high explosive molecules which have high detonation properties and are also insensitive. Presently 65 molecules were studied and 54 of them were handled for the first time in the literature. The detonation properties have been evaluated within the limitations of the Kamlet-Jacobs equations, based on the quantum chemically calculated densities and heat of formation values. It is found that there might be some candidates of relatively insensitive and high energy density materials among these 54 studied molecules so far not mentioned in the literature.
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Wang, Yanhua. "Theoretical Design of Molecular Photonic Materials." Doctoral thesis, Stockholm: Bioteknologi, Kungliga Tekniska högskolan, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-4333.
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Bunge, Scott Daniel. "The molecular design of metal amides." Diss., Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/30990.
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Lee, Devin. "Computer aided design for molecular inhibitors." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86881.
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In-silico methods used to aid the development of therapeutic drugs have gained utility in the recent past and continue to grow in importance. Small molecule drugs for the use in the treatment of type 2 diabetes were designed using computational methods to probe the active site of Dipeptidyl Peptidase IV (DPP-IV) and were subsequently synthesized and tested in-vitro. A number of pseudodipeptides formed from derivatives of tryptophan and proline were synthesized. The effects of a tetrazole group on the pyrrolidine of proline were studied, as well as the effect of protecting groups on the activity on DPP-IV. Exploring the effects of rigidifying the active dipeptides was next explored by attempting to synthesize the analogous bicyclic structures.In order to add to the knowledge in the realm of computation tools used for drug discovery, eight docking programs were used to screen a subset of a small molecule database, the Database of Useful Decoys (DUD). This study focused on the effects of protein flexibility, crystallographic waters and program/protein dependence on active compound identification accuracy. This knowledge gained on the efficacy of current docking programs in VS campaign on real world therapeutic targets will allow for more efficient drug design in the search for new therapeutic agents.
Les méthodes in-silico, utilisées pour faciliter le développement de composés thérapeutiques, ont dernièrement vu leur utilité croître en considérablement. Au cours de ce travail, une série de petites molécules visant le traitement du diabète de type 2 a été conçue en se servant de méthodes informatiques pour sonder le site actif de Dipeptidyl Peptidase IV (DPP-IV) et a, par la suite, été synthétisée et testée in-vitro.
Tout d'abord, de nombreux pseudo-dipeptides construits à partir de dérivés de tryptophane et proline ont été préparés. Les effets sur l'activité biologique d'un groupe tétrazole sur le groupe pyrrolidine de la proline ont été étudiés, ainsi que l'effet de la protection des groupes fonctionnels. L'étude de l'impact de la rigidification de ces dipeptides actives a ensuite été envisagée et une synthèse de structures bi-cycliques debutée.
Dans le but d'accroitre les connaissances sur les outils informatiques servant pour la découverte de médicaments, huit programmes d'amarrage ont été évalués sur une banque de données d'une petites molécules, "Database of Useful Decoys" (DUD). Nous nous sommes plus particulièrement intéressés à l'impact de la flexibilité des protéines, de l'eau cristallographique et du type de programme utilisé sur la fiabilité des résultats. Les données collectées au cours de cette étude va nous permettre de développer des programmes plus efficaces et par la suite permettre une meilleure fiabilité de ces programmes dans les campagnes de criblage virtuel futures qui auront pour but de trouver de nouveaux agents thérapeutiques.
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Frost, Jamie Michael. "Ligand design strategies for molecular nanomagnets." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/17990.
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This thesis describes the synthesis and magnetic characterisation of a series of polynuclear 3d and 3d/4f complexes built using phenolic oxime type ligands. Chapter two describes the reaction of salicylaldoxime and its derivatised analogues (R-saoH2) with the alkoxide containing co-ligands triethanolamine (TeaH3) and 2-(hydroxymethyl)pyridine (Hhmp), in the presence of Mn(II)/Ln(III) salts. This results in the formation of a family of sixteen [MnIII4LnIII2] clusters, which are structurally related to a previously studied [MnIII6] family of Single-Molecule Magnets (SMMs). The magnetic properties of the Ln = Y, Gd and Lu analogues can be qualitatively rationalised on the basis of a magneto-structural correlation (MSC), previously developed for MnIII alkoxide/oxime bridged dimers. Chapter three describes how the combination of two complimentary ligands, the phenolic oximes (R-SaoH2) and the diethanolamines (DeaH3), into one organic framework, creates new ligand types (H3L1 and H4L2) which can be used to construct a hexametallic MnIII wheel; [MnIII6Na(L1)6]Cl, the first example of a ferromagnetically coupled dodecametallic MnIII wheel;[MnIII 12(OMe)16(L2)4(O2CCMe3)4(MeOH)4], and the first example of a dodecametallic MnIII truncated tetrahedron; [MnIII12O4(H3L2)8(H2L2)4(TMA)4 (TMA = trianion of trimesic acid). Single crystal hysteresis measurements reveal both 3.2 and 3.3 to be SMMs at low temperature. Chapter four deals with the use of H4L2 in Cu coordination chemistry. Phenolic oximes are known to form monometallic complexes with CuII ions, as are the diethanolamines. However, the deliberate incorporation of one ligand onto the organic framework of the other permits the preparation of a family of [CuIIn] wheels (n = 4, 6, 8). In each case nearest neighbour interactions between CuII ions are shown to be strongly antiferromagnetic. DFT calculations suggest the origin of this interaction is related to the Cu-O-N-Cu dihedral angle, an observation which allows for the development of a theoretical MSC, that suggests a switch from antiferro- to ferro-magnetic exchange is possible at Cu-O-N-Cu angles > 60o.
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Wu, Qiong. "Synthesis of Polycatenanes Through Molecular Design." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1480950518125291.
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Deng, Wei-Qiao Kuppermann Aron. "Computation aided design in molecular nanotechnology /." Diss., Pasadena, Calif. : California Institute of Technology, 2004. http://resolver.caltech.edu/CaltechETD:etd-05282004-161503.
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Gallegos, Saliner Ana. "Molecular quantum similarity in QSAR: applications in computer-aided molecular design." Doctoral thesis, Universitat de Girona, 2004. http://hdl.handle.net/10803/7937.
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La present tesi està centrada en l'ús de la Teoria de Semblança Quàntica per a calcular descriptors moleculars. Aquests descriptors s'utilitzen com a paràmetres estructurals per a derivar correlacions entre l'estructura i la funció o activitat experimental per a un conjunt de compostos. Els estudis de Relacions Quantitatives Estructura-Activitat són d'especial interès per al disseny racional de molècules assistit per ordinador i, en particular, per al disseny de fàrmacs. Aquesta memòria consta de quatre parts diferenciades. En els dos primers blocs es revisen els fonaments de la teoria de semblança quàntica, així com l'aproximació topològica basada en la teoria de grafs. Ambdues teories es fan servir per a calcular els descriptors moleculars. En el segon bloc, s'ha de remarcar la programació i implementació de programari per a calcular els anomenats índexs topològics de semblança quàntica. La tercera secció detalla les bases de les Relacions Quantitatives Estructura-Activitat i, finalment, el darrer apartat recull els resultats d'aplicació obtinguts per a diferents sistemes biològics.
The present thesis is centred in the use of the Quantum Similarity Theory to calculate molecular descriptors. These molecular descriptors are used as structural parameters to derive correlations between the structure and the function or experimental activity for a set of compounds. Quantitative Structure-Activity Relationship studies are of special interest for the rational Computer-Aided Molecular Design and, in particular, for Computer-Aided Drug Design.
The memory has been structured in four differenced parts. The two first blocks revise the foundations of quantum similarity theory, as well as the topological approximation, based in classical graph theory. These theories are used to calculate the molecular descriptors. In the second block, the programming and implementation of Topological Quantum Similarity Indices must be remarked. The third section details the basis for Quantitative Structure-Activity Relationships and, finally, the last section gathers the application results obtained for different biological systems.
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Gopinath, Smitha. "Molecular design, process design and process synthesis of separation systems." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/59004.
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The simultaneous solution of the optimal process variables and optimal processing materials for a separation system is considered in this work. The processing materials (or molecules) may include, amongst others, reaction medium solvents, catalysts and mass separating agents. In this thesis, the processing materials to be designed are restricted to pure component solvents that act as mass separating agents. The design of fluid-fluid separation systems at steady state is considered in this work. In the first part of the thesis, the process topology is fixed and the process variables are continuous whereas the molecular variables, used to describe the solvent, are discrete. The computer aided molecular and process design problem (CAMPD) is a challenging mixed integer nonlinear programming problem (MINLP). A deterministic optimization algorithm tailored to the CAMPD of separation systems is proposed. Novel tests are embedded within an iterative MINLP solution framework. The tests may eliminate infeasible regions of both the molecular and process domain. The algorithm is applied to a case study of separation of carbon dioxide and methane. In the second part of the thesis, the scenario where the process variables are both continuous and discrete is considered. Chemical process synthesis is the activity of determining the optimal process units and their connectivity in a process. Process synthesis is a highly combinatorial problem which is challenging, even with fixed material decisions. A formulation for process synthesis problems is presented which addresses numerical singularities that are encountered when a process unit is not selected. The computer aided molecular and process synthesis (CAMPS) problem is considered next where the degrees of freedom include material and process synthesis decisions. An algorithm for CAMPS is developed by extending the CAMPD algorithm. A CAMPS case study of separation of butanol and water is modelled using the process synthesis formulation developed in this thesis. The tests can eliminate infeasible portions of the molecular domain and both continuous and discrete process domains. Both the CAMPD and CAMPS algorithms proposed here avert evaluations of infeasible primal problems and enhance convergence to solutions of challenging design problems.
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Zhou, Yangbin. "Molecular Design, Precise Synthesis and Solution Self-assembly of Molecular Patchy Particles." University of Akron / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=akron1460324862.
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Kayello, Hamed M. "Computer-Aided Molecular Design Using the Signature Molecular Descriptor: An Application to Design Novel Chemical Admixtures for Concrete." University of Akron / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=akron1405352312.
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Blank, Kerstin. "Molecular force sensors design, characterization and applications /." Diss., [S.l.] : [s.n.], 2006. http://edoc.ub.uni-muenchen.de/archive/00006085.
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Akpinar, Handan. "Design And Synthesis Of Functional Molecular Squares." Master's thesis, METU, 2006. http://etd.lib.metu.edu.tr/upload/12607452/index.pdf.
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Self-assembly has big importance in synthesizing supramolecular structures. Highly fluorescent molecular squares with boradiazaindacene (BODIPY) building blocks were obtained via usage of metal driven self-asembly. The boradiazaindacene units were connected with the Pd(II) complex unit enforcing a near-90 degree angle between the building blocks. Thus, we believe we have the first example of BODIPY carrying fluorescent squares. With collective experience in BODIPY chemistry in our group, we may have the first example of functionalizable molecular square. Self-assembled light harvesting systems will be ultimate biomimetic example of photosynthetic reaction center.
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Meehan, Stephen. "Enhancement of polyester properties through molecular design." Thesis, University of Reading, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590110.
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The aim of the work described in this thesis was to develop novel semi-crystalline, semi-aromatic polyester-based materials with improved thennal properties relative to their parent polymers, specifically poly(ethylene terephthalate) (PET) and po)y(ethylene-2,6-naphthalate) (PEN). This work involved the design and development of a small-scale (2-10 g) vacuum polyesterification rig, synthesis of a variety of suitable comonomers - both known and unknown - and the synthesis of a range of novel copolymers by incorporating these comanomers through melt-phase polycondensation. Several comonomers were synthesised which could potentially enforce are-entrant chain-fold through confonnational restrict ions. However, these comonomers typically hindered the crystallisability of the copolymers and had no significant effect on Tg• Double Tgs were apparent for a small number of these copolymer compositions. A wide range of imide-containing comonomers was synthesised and incorporated into both PET and PEN. The resulting novel copoly(ester-imide)s generally displayed enhanced Tgs but showed a reduction in crystallinity at levels of 5 to 15 mol% diimide. Annealing of these copolymers gave materials with a greater Xc. often close to those of their respective homopolymers. The diimide monomer N,N-bis-(2-hydroxyethyI)pyromeJlitic diimide (POI), incorporated at 5 mol% into PEN, gave a Tg 10°C higher as well as a T m 10°C lowerthen PEN, with a comparable value of Xc once annealed. Finally, a range of copolymers containing 3,3',4,4'-biphenyldiimide units were introduced into PET, PEN and poly(butylene-2,6-naphthalate) (PBN). Crystallinity was observed for all compositions investigated with PEN (2-25% comonomer), and the degree of crystallinity and rate of crystallisation increased progressively above 5 mol%. X-ray powder and fibre diffraction techniques revealed that compositions containing ~ 5 mol% diimide, annealed at 180°C, have a completely different crystalline structure from PEN itself. The new unit cell for this novel copolymer is monoclinic, space group C2/m, with two chains passing through the unit cell, and cell parameters a = 10.50, b = 6.85, c = 13.28 A, f3 = 141.6°
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Qiu, Song. "Molecular communication systems : design, modelling and experimentation." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/95162/.
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Molecular Communications (MC) is an increasingly attractive technique to enable the communication and networking of devices in environments where traditional communication techniques may not be suitable. MC has been used to convey information in both human society and in animal populations and been studied on both the microscale and the macroscale. On the basis of these studies, this thesis focuses on characterising MC channel models under different environments and examining the impact these models have on the communication performance. The thesis begins by reviewing the latest developments in MC including communication paradigm, channel models, modulation schemes and forward error correction codes. It then provides the comprehensive research methods used during the PhD, including the construction of complex propagation environments and molecular communication equipments, and explains the procedures of the experimentation. The thesis then goes on to analyse the channel model for static environment. A novel capture probability expression of a finite sized receiver and the performance metrics of bit error rate, throughput and round-trip-time are derived. Experimentally, the additive noise in the channel response was found to conform to a Nakagami distribution. Afterwards, the thesis characterises two dynamic channel models, namely, the fading distribution due to temperature fluctuations, which is validated by numerical simulations, and the mobile channel where both transmitter and receiver are in mobility and in order to combat transposition errors, positional-distance codes are applied. Furthermore, the energy model of the bacteria based mobile relay channel is proposed to demonstrate a superior energy efficiency. Finally, the thesis goes on to propose a potential application of MC to locate a hidden entity with an unknown location in a vast underwater search space. Two molecular messaging methods for location discovery are proposed: a chemical encoding messaging method, and a Rosenbrock gradient ascent algorithm. The two chemical methods are found to offer attractive performance trade-offs in complexity and robustness. To conclude, the potential future work on MC channel modelling is identified in complex geometric environments.
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Nomura, Yuta. "Nanogel artificial molecular chaperone : design and application." 京都大学 (Kyoto University), 2005. http://hdl.handle.net/2433/145393.
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Kyoto University (京都大学)0048
新制・課程博士
博士(工学)
甲第11235号
工博第2446号
新制||工||1328(附属図書館)
22844
UT51-2004-U440
京都大学大学院工学研究科合成・生物化学専攻
(主査)教授 青山 安宏, 教授 森 泰生, 教授 木村 俊作
学位規則第4条第1項該当
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Alves, Jessica. "Advanced photochemical reaction systems for molecular design." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/227734/1/Jessica_Alves_Thesis.pdf.
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Direct laser writing is a technique for printing complex 3D structures with high resolution by irradiating a photoresist in a two-photon process. Improved resolution and dynamic material properties of the printed structures is critical. Herein, advanced photochemical systems were investigated, potentially enabling dual-wavelength direct laser writing. Such systems consisting of organic photoswitches enable the formation of a single product only when irradiated with two wavelengths. A well-known class of photoswitches was investigated for this purpose and its chemistry was carefully explored. Further, photocatalysis combined with a photoswitch was identified as a possible strategy for the two-colour activated photoresist development.
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Willis, Peter G. "DESIGNING MOLECULAR RECOGNITION IN THE CONTEXT OF HYDROGEN BONDING AND MOLECULAR DYNAMICS." UKnowledge, 2001. http://uknowledge.uky.edu/gradschool_diss/279.
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The effect of hydrogen bonding on the conformation of organic moleculesunifies two projects in this thesis. In one project, the stability of the intramolecularhydrogen bond in derivatives of 2-guanidinobenzimidazole was studied bydynamic 1H NMR spectrometry. The impact that this intramolecular hydrogenbond had on the bond order of the neutral guanidino group and on the dynamicconformation of these aromatic structures was related to the concept of hydrogenbond-assisted resonance. In another project, an oligomer possessing repetitiveconformation and capable of much inter- and intramolecular hydrogen bondingwas designed and synthesized. The sensitivity of this oligomer to changes inanion concentration, as well as its own propensity to self-aggregate weremeasured.Hydrogen bonds found in many biological oligomers are connected thougha system of conjugated bonds. Guanidinobenzimidazole is a conjugated systemof carbon and nitrogen, connected by an intramolecular hydrogen bond. Severalderivatives of guanidinobenzimidazole were synthesized, and the effect ofseveral simple alkyl for hydrogen substitutions were studied.Guanidinobenzimidazole was used as a model to study what effect theconjugation and the intramolecular hydrogen bond have on each other.The formation of redundant low energy hydrogen bonds is universal inbiological oligomers. In DNA and RNA multiple hydrogen bonds are formed witha typical energy contribution of only 1-2 kcal/mol. Individually, these interactionsdo not give the biological oligomers their conformational stability, but togetherthey are very stable. The urea and amide based oligomers designed in the workand discussed in the thesis should form multiple hydrogen bonds withthemselves and/or with anionic guests. Chiral oligoureas were designed topossess this characteristic of cooperative conformation that so many biologicaloligomers and polymers share.
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Rosik, Daniel. "On the Design of Affibody Molecules for Radiolabeling and In Vivo Molecular Imaging." Doctoral thesis, KTH, Molekylär Bioteknologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-117862.
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Affibody molecules have lately shown great potential as tools for in vivo molecular imaging. These small, 3-helical bundles, with their highly stable protein scaffold, are well suited for the often harsh conditions of radiolabeling. Their small size allows for rapid clearance from the blood circulation which permits the collection of images already within hours after injection. This thesis includes four papers aimed at engineering different variants of a HER2-binding Affibody molecule to enable effective and flexible radiolabeling and enhancing the molecular imaging in terms of imaging contrast and resolution. In paper I an Affibody molecule was engineered to function as a multifunctional platform for site-specific labeling with different nuclides for radionuclide imaging. This was done using only natural amino acids, thereby allowing for both synthetic and recombinant production. By grafting the amino acid sequence -GSECG to the C-terminal of our model-protein, a HER2-binding Affibody molecule, we enabled site specific labeling with both trivalent radiometals and with 99m Tc. Maleim-ide-DOTA was conjugated to the cysteine residue for labeling with 111 In, while the peptide sequence was able to chelate 99m Tc directly. This approach can also be used for site-specific labeling with other probes available for thiol-chemistry, and is applicable also to other protein scaffolds. In paper II we investigated the impact of size and affinity of radiolabeled Affibody molecules on tumor targeting and image contrast. Two HER2-targeting Affibody molecules, a two-helix (~5 kDa) and a three-helix (~7 kDa) counterpart, were synthetically produced, labeled with 111 In via chelation by DOTA and directly compared in terms of biodistribution and targeting properties. Results showed that the smaller variant can provide higher contrast images, at the cost of lower tumor uptake, in high-expressing HER2-tumors. However, neither the tumor uptake nor the contrast of the two-helix variant is sufficient to compete with the three-helix molecule in tumors with low expression of HER2. In paper III and IV we were aiming to find methods to improve the labeling of Affibody molecules with 18 F for PET imaging. Current methods are either complex, time-consuming or generate heavily lipophilic conjugates. This results in low yields of radiolabeled tracer, low specific activity left for imaging, undesirable biodistribution or a combination thereof. In paper III we demonstrate a swift and efficient 2-step, 1-pot method for labeling HER2-binding Affibody molecules by the formation of aluminum 18 F-fluoride (Al 18 F) and its chelation by NOTA, all in 30 min. The results show that the 18 F-NOTA-approach is a very promising method of labeling Affibody molecules with 18 F and further investigation of this scheme is highly motivated. In the last paper we pursued the possibility of decreasing the high kidney retention that is common among small radiotracers with residual-izing radiometabolites. In this work 18 F-4-fluorobenzaldehyde (FBA) was conjugated to a synthetic HER2-targeting Affibody molecule via oxime ligation. However, to avoid elevated liver retention, as seen in previous studies with this kind of label, a hydrophilic triglutamyl spacer between the aminooxy moiety and the N-terminal was introduced. A comparison of the two constructs (with and without the triglutamyl spacer) showed a clear reduction of retention in both kidney and liver in NMRI mice at 2 h p.i. when the spacer was included. In the light of these promising results, further studies including tumor-bearing mice, are in preparation.QC 20130203
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Hadjigeorgiou, Christina. "Molecular modelling studies on bidentate iron chelators." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298845.
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Austin, Nick Donnelly. "Tools for Computer-Aided Molecular and Mixture Design." Research Showcase @ CMU, 2017. http://repository.cmu.edu/dissertations/894.
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This thesis explores mathematical optimization techniques to address the computeraided molecular and mixture design problems (CAMD/CAMxD). In particular, we leverage the power of mixed-integer linear programs (MILPs) to quickly and efficiently design over the massive chemical search space. These MILPs, when coupled with state-ofthe- art derivative-free optimization (DFO) methods, make for an efficient optimization strategy when designing mixtures of molecules or when considering a single molecule design problem that involves difficult thermodynamics or process models. In the first chapter, we provide a very general overview of the field of CAMD as addressed from the perspective of mathematical optimization. We discuss many relevant quantitative structure-property relationships (QSPRs) and provide constraints typically used in CAMD/CAMxD optimization problems. The second chapter introduces our DFO-based molecular/mixture design algorithm and describes how this approach enables a much greater molecular diversity to be considered in the search space as compared to traditional methods. Additionally, this chapter looks at a few case studies relevant to crystallization solvents and provides a detailed comparison of 27 different DFO algorithms for solving these problems. The third chapter introduces COSMO-RS/-SAC as alternatives to UNIFAC as the method used to capture mixture thermodynamics for a variety of CAMD/CAMxD problems. To fully incorporate COSMO-RS/-SAC into CAMD, we introduce group contribution (GC) methods for estimating a few necessary parameters for COSMO-based methods. We demonstrate the utility of COSMO-RS/-SAC in a few case studies for which UNIFAC-like methods are insufficient. In the fourth chapter, we investigate reaction solvent design using COSMO-based methods. COSMO-RS is particularly suitable for these problems as they allow for modeling of many relevant species in chemical reactions (transition states, charges, etc.) directly at the quantum level. This information can be immediately passed to the CAMD problem. We investigate a number of solvent design problems for a few difficult reactions. We summarize the work and provide a few future directions in the final chapter. Overall, this thesis serves to push the field of CAMD forward by introducing new methods to more efficiently explore the massive chemical search space and to enable a few new classes of problems which were previously untenable.
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Skalic, Miha 1990. "Deep learning for drug design : modeling molecular shapes." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/667503.
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Designing novel drugs is a complex process which requires finding molecules in a vast chemical space that bind to a specific biomolecular target and have favorable physio-chemical properties. Machine learning methods can leverage previous data and use it for new predictions helping the processes of selection of molecule candidate without relying exclusively on experiments. Particularly, deep learning can be applied to extract complex patterns from simple representations. In this work we leverage deep learning to extract patterns from three-dimensional representations of molecules. We apply classification and regression models to predict bioactivity and binding affinity, respectively. Furthermore, we show that it is possible to predict ligand properties for a particular protein pocket. Finally, we employ deep generative modeling for compound design. Given a ligand shape we show that we can generate similar compounds, and given a protein pocket we can generate potentially binding compounds.El disseny de drogues novells es un procés complex que requereix trobar les molècules adequades, entre un gran ventall de possibilitats, que siguin capaces d’unir-se a la proteïna desitjada amb unes propietats fisicoquímiques favorables. Els mètodes d’aprenentatge automàtic ens serveixen per a aprofitar dades antigues sobre les molècules i utilitzar-les per a noves prediccions, ajudant en el procés de selecció de molècules potencials sense la necessitat exclusiva d’experiments. Particularment, l’aprenentatge profund pot sera plicat per a extreure patrons complexos a partir de representacions simples. En aquesta tesi utilitzem l’aprenentatge profund per a extreure patrons a partir de representacions tridimensionals de molècules. Apliquem models de classificació i regressió per a predir la bioactivitat i l’afinitat d’unió, respectivament. A més, demostrem que podem predir les propietats dels lligands per a una cavitat proteica determinada. Finalment, utilitzem un model generatiu profund per a disseny de compostos. Donada una forma d’un lligand demostrem que podem generar compostos similars i, donada una cavitat proteica, podem generar compostos que potencialment s’hi podràn unir.
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Kambe, Yusuke. "Molecular Design of Silk Fibroin for Functional Scaffolds." 京都大学 (Kyoto University), 2013. http://hdl.handle.net/2433/174922.
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Calabrò, Gaetano. "Accelerating molecular simulations : implication for rational drug design." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/16439.
Full textAbstract:
The development and approval of new drugs is an expensive process. The total cost for the approval of a new compound is on average 1.0 - 1.2 billion dollars and the entire process lasts about 12 - 15 years. The main difficulties are related to poor pharmacokinetics, lack of efficacy and unwanted side effects. These problems have naturally led to the question if new and alternative methodologies can be developed to find reliable and low cost alternatives to existing practices. Nowadays, computer-assisted tools are used to support the decision process along the early stages of the drug discovery path leading from the identification of a suitable biomolecular target to the design/optimization of drug-like molecules. This process includes assessments about target druggability, screening of molecular libraries and the optimization of lead compounds where new drug-like molecules able to bind with sufficiently affinity and specificity to a disease-involved protein are designed. Existing computational methods used by the pharmaceutical industry are usually focused on the screening of library compounds such as docking, chemoinformatics and other ligand-based methods to predict and improve binding affinities, but their reliable application requires improvements in accuracy. New quantitative methods based on molecular simulations of drug binding to a protein could greatly improve prospects for the reliable in-silico design of new potent drug candidates. A common parameter used by medicinal chemists to quantify the affinity between candidate ligands and a target protein is represented by the free energy of binding. However, despite the increased amount of structural information, predicting binding free energy is still a challenge and this technique has found limited use beyond academia. A major reason for limited adoption in the industry is that reliable computer models of drug binding to a protein must reproduce the change in molecular conformations of the drug and protein upon complex formation and this includes the correct modelling of weak non-covalent interactions such as hydrogen bonds, burials of hydrophobic surface areas, Van der Waals interactions, fixations of molecular degrees of freedom solvation/desolvation of polar groups and different entropy contributions related to the solvent and protein interactions. For several classes of proteins these phenomena are not easy to model and often require extremely computationally intensive simulations. The main goal of the thesis was to explore efficient ways of computing binding affinities by using molecular simulations. With this aim, novel software to compute relative binding free energies has been developed. The implementation is based on alchemical transformations and it extended a preexisted piece of software Sire, a molecular modeling framework, by using the OpenMM APIs to run fast molecular dynamics simulations on the latest GPGPU technology. This new piece of software has equipped the scientific community with a flexible and fast tool, not only to predict relative binding affinities, but also a starting point to develop new sampling methods for instance hybrid molecular dynamics and Monte Carlo. The implementation has been validated on the prediction of relative hydration free energy of small molecules, showing good agreement with experimental data. In addition, non-additive effects to binding affinities in series of congeneric Thrombin inhibitors were investigated. Although excellent agreement between predicted and experimental relative binding affinities was achieved, it was not possible to accurately predict the non-additivity levels in most of the examined inhibitors, thus suggesting that improved force fields are required to further advance the state-of-the art of the field.
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Rolland, de Denus Christine Marie. "Controlled molecular design and polymerization of polyaromatic ethers." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq23656.pdf.
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Jin, Albert Yongwon. "Biologically driven molecular modeling for anticonvulsant drug design." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0007/NQ42948.pdf.
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Rizvi, Syed Asad Ali. "Design of Novel Molecular Micelles for Capillary Electrophoresis." Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/chemistry_diss/5.
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The research presented in this dissertation involves the synthesis, characterization, and application of novel anionic and cationic chiral molecular micelles in capillary electrophoresis (CE) for the separation of diverse chiral compounds. Chapter 1 presents brief overview of the surfactants, micelle polymer, CE and micellar electrokinetic chromatography (MEKC). Chapter 2 describes the simultaneous enantioseparation of eight single chiral center â-blockers using two novel leucine and isoleucine based polymeric surfactants. The simultaneous enantioseparation of multichiral center bearing â-blockers, nadolol and labetalol is described in chapter 3. A synergistic approach, using a combination of polysodium N-undecenoxycarbonyl-L-isoleucinate (poly-L-SUCIL) and sulfated â-CD showed dramatic enantioseparation of four stereoisomers of nadolol. On the other hand for labetalol, enantiomeric separation remains unaffected using the dual chiral selector system. Chapter 4 deals with the enantiomeric separation of the binaphthyl derivatives that was found to be influenced by pH, type and concentration of the background electrolyte as well as concentration of the polymeric surfactant. In chapter 5, characterization of five alkenoxy leucine-based surfactants with variations in chain length (C8-C11), polymerization concentration and degree of polymerization showed significant effects on the chiral resolution and efficiency of hydrophobic â-blockers. The synthesis and characterization of two positively charged amino acid derived chiral ionic liquids (ILs) and their corresponding polymers is presented in chapter 6. Chiral separation of two acidic analyte (difficult to resolve with anionic micelles) can be achieved with both monomers and polymers of ILs. In chapter 7, the synthesis and detailed characterization of three pH independent amino acids derived (L-leucinol, L-isoleucinol and L-valinol) sulfated chiral polymeric surfactants is presented. These chiral sulfated surfactants are thoroughly characterized and the morphological behavior of polymeric sulfated surfactants is revealed using cryogenic high-resolution electron microscopy. The work clearly demonstrates for the first time the superiority of chiral separation in MEKC coupled to mass spectrometry at low pH. Finally, in chapter 8, six amino acid derived chiral surfactants with carboxylate and sulfate head groups were compared for enantioseparation of broad range of structurally diverse racemic compounds at neutral and basic pH conditions.
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Montgomery, H. J. "Design of new sensor platforms for molecular recognition." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558212.
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A series of bipyridine and pyridine ligands have been prepared and fully characterised. These are 5- bromobutyr-2,2'-bipyridine (L 1), (2,2'-Bipyridin-5-ylmethyl)-5-(1 ,2-dithiolan-3-yl)pentanoate (L2) N-(2,2'- bipyridin-5-ylmethyl)-5-(1 ,2-dithiolan-3-yl)pentanamide (L3), pyridin-3-ylmethyl-5-(1,2-dithiolan-3- yl)pentanoate (L4) pyridin-4-ylmethyl-5-(1 ,2-dithiolan-3-yl)pentanamide (LS) and ethyl 5-(1,2-dithiolan-3- yl)pentanoate (L6). Their Re(l) and RU(lI) complexes have also been prepared and characterised in most cases. The photophysical properties of these complexes have been investigated showing expected intense . emission. The behaviour of a variety of these ligands and complexes has been studied on a colloidal silver surface, analysed by Surface Enhanced (Resonance) Raman Spectroscopy (SE(R)RS). Concentration dependent behaviour was observed for L2 and L3. A relatively low intensity of the SERS signal at the highest concentrations was attributed to a combination of interference of fluorescence from species in solution and high surface coverage of the nanoparticles preventing the formation of silver-bipyridine complexes. At the optimum concentration we propose the formation of silver-bipyridine complexes which display a resonance enhanced component of the SERS signal. At lower concentrations a simple lack of substrate capable of giving a signal results in a reduction in the observed peak intensity again. Similar behaviour was also observed for the respective rhenium(l) complexes, [Re(COh(L2)Br] and [Re(COh(l3) Br] while preliminary work also indicated the same behaviour in the charged rhenium(l) complexes [Re(COh(bpy)(py)f and [Re(COh(bpy)(LS)r. These insights may enable the development of the system for future sensing applications. Complex [Re(COh(L2)Br] and [Re(COh(bpy)Br] showed selective changes in its photophysical properties in the presence of Hg2+ ions when experiments were carried out in acetonitrile solution. Detailed studies of the system suggest that an exchange of the Br ligand fora CH3CN ligand takes place through an intermediate species, with formation of the charged complex [Re(COh(L2)(CH3CN)f and [Re(COh(bpy) (CH3CN)1 irrespective of the counter-ion (either CI04- or N03-). Similar behaviour was not observed with a range of other metal cations.
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Lui, Chih-Hung. "Molecular design and synthesis of coumarin fluorescent dyes." Thesis, Heriot-Watt University, 2000. http://hdl.handle.net/10399/572.
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Kilvington, Simon Robert. "The application of computational techniques in molecular design." Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243045.
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Ruzette, Anne-Valérie G. (Anne-Valérie Geneviève). "Molecular design of ordering transitions in block copolymers." Thesis, Massachusetts Institute of Technology, 2000. http://hdl.handle.net/1721.1/55062.
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Thesis (Ph.D.)--Massachusetts Institute of Technology, School of Architecture and Planning, Program in Media Arts and Sciences, 2000.Vita.
Includes bibliographical references (p. 201-216).
The tendency of block copolymers (BCP's) to microphase separate at the molecular level, producing a wide array of ordered nanostructures, is of particular interest from an engineering standpoint due to the unique mechanical, optical or electrical properties that ensue. Upon considering the potential applications of these materials, however, one limitation arises from the lack of control over bulk thermodynamics and the appearance of order/disorder (solid-like/liquid-like) transitions in these materials. To address this problem, this thesis aims to, firstly, develop a more quantifiable understanding of the molecular factors governing BCP phase behavior, and, secondly, use that knowledge to molecularly engineer new BCP's with enhanced processibility. While most BCP's microphase separate upon cooling through an upper disorder-to-order transition (UDOT), polystyrene-block-poly n-butyl methacrylate, PS-b-PBMA, undergoes ordering upon heating through a lower disorder-to-order transition (LDOT). Preliminary studies on this material revealed a unique pressure sensitivity of this ordering transition. By applying pressure, this material could be forced into the segmentally mixed liquid state, implying "baroplasticity", a highly attractive property from a processing standpoint. To better understand the molecular origin of this behavior, the bulk thermodynamics of a family of BCPs formed from styrene and a homologous series of n-alkyl methacrylates (PS-b-PnAMA, n ranging from 1 to 12) was investigated, both as a function of pressure and temperature. The results of this study reveal an unexpected, though systematic, dependence of the phase behavior of these BCP's on monomer architecture. In short, over a certain range of alkyl side chain length, PS-b-PnAMA block copolymers are marginally compatible and exhibit unexpectedly large pressure coefficients for the ordering transition, ranging from 60 to 150°C/kbar. In an attempt to identify molecular parameters responsible for these thermodynamic trends, as well as those displayed by other systems reported in the literature, combined group contribution/lattice fluid model calculations of the cohesive properties of the corresponding homopolymers are performed. Based on this analysis, the homopolymer mass density is proposed as a macroscopic parameter that appears to govern phase behavior in weakly interacting block copolymers or polymer blends. Using this new criterion, a simple tool for the molecular design of phase behavior into weakly interacting BCP's is identified, which is successfully used to engineer "baroplastic" behavior into several new systems of commercial relevance, including elastomers and adhesives based on styrene and low Tg acrylates. In light of the improved understanding of BCP phase behavior emerging from these studies, a simple phenomenological free energy expression is proposed for compressible polymer mixtures, that can be extended to block copolymers. Its ability to predict qualitative phase diagrams for the systems investigated in this thesis as well as many other polymer pairs is demonstrated. Using this expression, basic principles regarding polymer thermodynamics are outlined.
by Anne-Valérie G. Ruzette.
Ph.D.
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Diao, Ying Ph D. Massachusetts Institute of Technology. "Design of polymeric substrates for controlled molecular crystallization." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/70408.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 171-175).
It is essential to control crystallization in many areas of science and technology, such as the production of pharmaceuticals, pigments, concrete, semiconductors, as well as the formation of biominerals. In most practical circumstances, crystallization starts with heterogeneous nucleation at a foreign surface. Despite its widespread occurrence, mechanistic understanding of the role of a surface in heterogeneous nucleation is limited, especially in a solution environment. My thesis aims at elucidating the roles of surface chemistry and nanostructure on nucleation to enable rational design of surfaces for controlling crystallization from solution. To this end, I systematically investigated the role of surface chemistry, morphology, in particular porous structures of various polymeric materials on heterogeneous nucleation using small organic molecules as model compounds. I have demonstrated quantitatively the significance of surface chemistry to nucleation kinetics using a variety of polymer surfaces. By tuning the surface composition of the polymers, aspirin nucleation was promoted by up to an order of magnitude compared to the bulk. Further mechanistic investigations revealed that, macroscopically, it is through interfacial free energies that the surfaces influence the surface nucleation activity. Equipped with nucleation induction time statistics as a powerful tool, I found that nanoscopic pores of 50-100 nm accelerated nucleation by up to two orders of magnitude compared with surfaces without pores. Moreover, I demonstrated for the first time that the shape of surface nanopores is essential in determining the nucleation behavior, using lithographic methods for nanopatterning the polymer films. A molecular mechanism was further proposed based on additional mechanistic investigations. Furthermore, the nanoconfinement effect on nucleation was studied using polymeric microgels with tunable nanostructures and chemistry, whose mesh sizes range from 0.7-2 nm. We presented the first experimental evidence for the existence of an optimum confinement size at which the rate of nucleation was dramatically enhanced by up to four orders of magnitude. The degree of nucleation enhancement depends on the extent of polymer-solute interactions, whose role was elucidated from the perspective of adsorptive partitioning and nucleation-templating effect. In addition, the microgel nanostructure was also shown to play an important role in determining the crystal polymorphism of pharmaceutical compounds.
by Ying Diao.
Ph.D.
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Song, Changsik. "Design and synthesis of molecular actuators and sensors." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/41554.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2007.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Includes bibliographical references.
To date, the most successful conducting polymer actuators are based on polypyrrole, which operates through incorporating and expelling counterions and solvent molecules to balance the charges generated by electrochemical stimuli (swelling mechanism). Although significant progress has been made, there still exists a need for developing new materials that would overcome the intrinsic limitations in the swelling mechanism, such as slow diffusion rate, limited expansion volume, etc. Our group has contributed this area with a different approach -- lecular mechanisms, which utilize a dimensional change of a single polymer chain. We propose two types of molecular mechanisms: contracting and expanding. We proposed earlier a calix[4]arenebased molecular actuator for the contracting mechanism, in which p-dimer formation was proposed as a driving force. In this dissertation, we first confirm by model studies that p-dimer formation can indeed be a driving force for the calix[4]arene-based system. We propose another molecular hinge, binaphthol moiety, for the contracting model. The syntheses of polymers with binaphthols and their characterization, including signatures of oligothiophene interactions, are described. Due to its chirality, we examined the possibilities of the binaphthol polymer as a chiral amine sensor. To create actuators that make use of the expanding model, we propose new conjugated seven-membered ring systems with heteroatoms (thiepin with sulfur and azepine with nitrogen) and their syntheses and characterization will be described. Inspired by the fact that sulfoxide has very low extrusion barrier in the related system, we applied the thiepin molecules to create a peroxide sensor.
(cont.) In addition, during the investigation of phenol functional groups in conducting polymers, we found interesting properties that strategic positioning of phenol groups can render a conjugation-broken meta-linked system just as conductive as a fully conjugated para-linked isomeric system.
by Changsik Song.
Ph.D.
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Truong, Tran N. B. "Molecular design for controlling morphology in organic electronics." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/120904.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2018.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 140-158).
Chapter 1 gives an introduction to the structure, operation mechanism, performance parameters, and challenges of organic photovoltaic devices. We also discuss some strategies to improve the performance of photovoltaics, with an emphasis on morphology control in polymer bulk-heterojunction devices. Chapter 2 describes the synthesis of a class of polymer additives for bulk-heterojunction (BHJ) solar cells based on an extended triptycene-containing unit. The incorporation of these additives on BHJ photovoltaic devices based on PTB7 and PC71BM leads to an increase in power conversion efficiencies of 10-20%. We also found that the additives produce more consistent performance in devices, minimizing variation from processing conditions. Chapter 3 presents a modular synthetic route to access functionalized 2,5-di(thiophen-2- y1)- 1-H-arylpyrroles (SNS) from readily available starting materials. We demonstrated the use of this building block in the synthesis of conjugated polymers with high thermal stability and solubility. Characterization of the polymers reveals a correlation between molecular packing and charge carrier mobility. Chapter 4 discusses strategies to enhance conjugation in organic electronic materials, using 2,5-di(thiophenyl)-N-arylpyrrole (SNS) as a model system. The first section describes synthetic routes to access a novel polycyclic heteroaromatic building block via intramolecular cyclization reactions. The second section explores the electrochemical properties of SNS units for the opportunity to enhance conjugation via electrochemical methods.
by Tran N. B. Truong.
Ph. D.
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Gupta, Chetali. "Polymer-grafted Lignin: Molecular Design and Interfacial Activities." Research Showcase @ CMU, 2017. http://repository.cmu.edu/dissertations/766.
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The broader technical objective of this work is to develop a strategy for using the biopolymer lignin in a wide variety of surfactant applications through polymer grafting. These applications include emulsion stabilizers, dispersants and foaming agents. The scientific objective of the research performed within this thesis is to understand the effect of molecular architecture and polymer grafting on the interfacial activity at the air-liquid, liquid-liquid and solid-liquid interface. Research has focused on designing of these lignopolymers with controlled architecture using polyethylene glycol, poly(acrylic acid) and polyacrylamide grafts. The interfacial activity for all polymer grafts has been tested at all three interfaces using a broad range of techniques specific to the interface. Results have shown that the hydrophobicity of the lignin core is responsible for enhanced interfacial activity at the air-liquid and liquid-liquid interface. Conversely, improved hydrophilicity and “electrosteric” interactions are required for higher interfacial activity of the lignin at the liquid-solid interface. The high interfacial activity of the polymer-grafted lignin observed in the air-liquid and liquid-liquid interfaces not only resulted in viscosity reduction but also strength enhancement at the liquid-solid interface. The broader implication of this study is to be able to predict what chemical functionalities need to be adjusted to get the desired viscosity reduction.
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Pavurala, Naresh. "Oral Drug Delivery -- Molecular Design and Transport Modeling." Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/53505.
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One of the major challenges faced by the pharmaceutical industry is to accelerate the product innovation process and reduce the time-to-market for new drug developments. This involves billions of dollars of investment due to the large amount of experimentation and validation processes involved. A computational modeling approach, which could explore the design space rapidly, reduce uncertainty and make better, faster and safer decisions, fits into the overall goal and complements the product development process. Our research focuses on the early preclinical stage of the drug development process involving lead selection, optimization and candidate identification steps. Our work helps in screening the most favorable candidates based on the biopharmaceutical and pharmacokinetic properties. This helps in precipitating early development failures in the early drug discovery and candidate selection processes and reduces the rate of late-stage failures, which is more expensive.
In our research, we successfully integrated two well-known models, namely the drug release model (dissolution model) with a drug transport model (compartmental absorption and transit (CAT) model) to predict the release, distribution, absorption and elimination of an oral drug through the gastrointestinal (GI) tract of the human body. In the CAT model, the GI tract is envisioned as a series of compartments, where each compartment is assumed to be a continuous stirred tank reactor (CSTR). We coupled the drug release model in the form of partial differential equations (PDE's) with the CAT model in the form of ordinary differential equations (ODE's). The developed model can also be used to design the drug tablet for target pharmacokinetic characteristics. The advantage of the suggested approach is that it includes the mechanism of drug release and also the properties of the polymer carrier into the model. The model is flexible and can be adapted based on the requirements of the clients. Through this model, we were also able to avoid depending on commercially available software which are very expensive.
In the drug discovery and development process, the tablet formulation (oral drug delivery) is an important step. The tablet consists of active pharmaceutical ingredient (API), excipients and polymer. A controlled release of drug from this tablet usually involves swelling of the polymer, forming a gel layer and diffusion of drug through the gel layer into the body. The polymer is mainly responsible for controlling the release rate (of the drug from the tablet), which would lead to a desired therapeutic effect on the body.
In our research, we also developed a molecular design strategy for generating molecular structures of polymer candidates with desired properties. Structure-property relationships and group contributions are used to estimate the polymer properties based on the polymer molecular structure, along with a computer aided technique to generate molecular structures of polymers having desired properties. In greater detail, we utilized group contribution models to estimate several desired polymer properties such as grass transition temperature (Tg), density (ρ) and linear expansion coefficient (α). We subsequently solved an optimization model, which generated molecular structures of polymers with desired property values. Some examples of new polymer repeat units are - [CONHCH₂ - CH₂NHCO]n -, - [CHOH - COO]n -. These repeat-units could potentially lead to novel polymers with interesting characteristics; a polymer chemist could further investigate these. We recognize the need to develop group contribution models for other polymer properties such as porosity of the polymer and diffusion coefficients of water and drug in the polymer, which are not currently available in literature.
The geometric characteristics and the make-up of the drug tablet have a large impact on the drug release profile in the GI tract. We are exploring the concept of tablet customization, namely designing the dosage form of the tablet based on a desired release profile. We proposed tablet configurations which could lead to desired release profiles such as constant or zero-order release, Gaussian release and pulsatile release. We expect our work to aid in the product innovation process.Ph. D.
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Gardlik, Matthew M. "Design, synthesis, and encapsulation processes of molecular baskets." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243536105.
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Li, Fusheng. "Design of Water Splitting Devices via Molecular Engineering." Doctoral thesis, KTH, Organisk kemi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-181107.
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Converting solar energyto fuels such as hydrogen by the reaction of water splitting is a promising solution for the future sustainable energy systems. The theme of this thesis is to design water splitting devices via molecular engineering; it concerns the studies of both electrochemical-driven and photo-electrochemical driven molecular functional devices for water splitting. The first chapter presents a general introduction about Solar Fuel Conversion. It concerns molecular water splitting catalysts, light harvesting materials and fabrication methods of water splitting devices. The second chapter describes an electrode by immobilizing a molecular water oxidation catalyston carbon nanotubes through the hydrophobic interaction. This fabrication method is corresponding to the question: “How to employ catalysts in functional devices without affecting their performances?” In the third chapter, molecular water oxidation catalysts were successfully immobilized on glassy carbon electrode surface via electrochemical polymerization method. The O-O bond formation pathways of catalysts on electrode surfaces were studied. This kinetic studyis corresponding to the question: “How to get kinetic information of RDS whena catalyst is immobilized on the electrode surface?” Chapter four explores molecular water oxidation catalysts immobilized on dye-sensitized TiO2 electrodeand Fe2O3 semiconductor electrode via different fabrication methods. The reasons of photocurrent decay are discussed and two potential solutions are provided. These studies are corresponding to the question: “How to improvethe stability of photo-electrodes?” Finally, in the last chapter, two novel Pt-free Z-schemed molecular photo-electrochemical cells with both photoactive cathode and photoactive anode for visible light driven water splitting driven were demonstrated. These studies are corresponding to the question: “How to utilizethe concept of Z-schemein photosynthesis to fabricate Pt-free molecular based PEC cells?QC 20160129
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Reynolds, Eric Wesley. "Molecular model development for implantable artificial kidney design." Connect to resource, 2009. http://hdl.handle.net/1811/36979.
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Gardlik, Matthew Michael. "Design, synthesis, and encapsulation processes of molecular baskets." Columbus, Ohio : Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1243536105.
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Liu, Junxian. "Molecular Design of High-Performance Materials for Electrocatalysis." Thesis, Griffith University, 2022. http://hdl.handle.net/10072/416315.
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The development of green and efficient electrocatalysis, which targets the generation and storage of renewable energy by transforming electrical energy to chemical energy, is strongly driven by the challenges we face in increasing energy demand. Consequently, great efforts have been made in exploring efficient electrocatalysts. The conventional trial-and-error approach for electrocatalysts is timeconsuming due to the lack of direct information regarding the atomic-scale properties of electrocatalysts and the underlying elementary reaction mechanisms. To date, the rational molecular design of high-performance electrocatalysts has been extensively used. However, most of these computational studies are still in their infancy and more reliable modelling of electrochemical processes is needed to bridge the gap between experiments and theory. This thesis aims to utilize structural engineering at the atomic scale to develop high-performance electrocatalysts for hydrogen evolution reaction (HER) and chlorine evolution reaction (CER), and model the external factors of the operating environment to provide a better description of electrocatalytic processes.
The general background and objectives of this PhD project are presented in Chapter 1. The recent progress in numerical modelling of electrochemical reactions and processes is discussed in Chapter 2. The importance of theoretical identification and understanding of catalytic active sites is highlighted in this chapter. The computational method employed in this project is the density functional theory (DFT), which has been demonstrated to achieve increasing success in the description and understanding of the II complexity of electrocatalysis. Chapter 3 provides a short introduction of the DFT method, including its origin, development, and implementation.
Chapters 4-7 present all the research work completed for this project. As metalorganic frameworks (MOFs) are considered a large family of low-dimensional materials, a comprehensive computational study was conducted to investigate the structural properties and electronic properties of one-dimensional (1D) transition metalbased dithiolene MOFs. Their high electrical conductivities offer the potential for electrocatalytic hydrogen evolution, which is examined with the consideration of electrolyte effects in Chapter 4. As the one of main industrial reactions, CER electrolysis is challenging due to the selectivity of Cl2. This can be ascribed to the unavoidable oxygen evolution from the noble metal-based dimensionally stable anodes (DSAs) used in industry. To this end, six TMN4 complex embedded graphene (TMN4@G) single-atom catalysts (SACs) were systematically investigated in Chapter 5. The DFT results predicted that NiN4@G is a promising candidate for efficiently and selectively catalyzing chlorine evolution in acidic solution. Chapter 6 theoretically studied the performance of CER for eight two-dimensional (2D) semiconducting group- VA monolayers with α and β phases. It is suggested that β-arsenene monolayer exhibits high activity and selectivity of gaseous Cl2 generation by virtue of the expected Cl* precursor. In Chapter 7, three low-dimensional Fe/Co/Ni−dithiolene MOFs were purposely selected due to their acid resistance and comprehensively investigated for electrocatalytic CER. The calculated results demonstrate that Ni-based dithiolene MOF can efficiently catalyze the CER via the Cl* pathway.
This thesis makes significant contributions to the theoretical understanding of electrochemical processes, materials science, and electrochemical energy conversion and storage through: (i) demonstrating the importance of electronic configurations of metal cations in the electrical conductivities of transition metal-dithiolene MOFs; (ii) proposing a novel strategy for optimizing the electronic structure of materials on the basis of the resonant charge transfer mechanism; (iii) predicting efficient lowdimensional electrocatalysts for Cl2 evolution with the Cl* intermediate rather than the ClO* intermediate; and (iv) investigating the interactions between adsorbates and catalysts to provide a new descriptor for the discovery of high-performance CER electrocatalysts. It is worth noting that the studies on the electrocatalytic properties of low-dimensional materials are still in the early stage. As such, more accurate models and approaches combined with multiscale simulation are needed in future studies, such as the modelling of the electrode-electrolyte interface, dynamic solvent, and electrical double layer.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
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Burt, Catherine. "A theoretical investigation of bioisosterism by molecular similarity." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291094.
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Tran, Thuy. "Molecular Imaging of HER2 Expression using Synthetic Affibody Molecules : Design, Synthesis and Biological Evaluation." Doctoral thesis, Uppsala universitet, Enheten för biomedicinsk strålningsvetenskap, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-99248.
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Molecular imaging is an emerging multidisciplinary field that addresses the visualisation of diseases at the cellular and molecular levels. This thesis focuses on the development of a synthetic Affibody molecule-based imaging tracer for the detection of HER2 expression in malignant tumours. Papers I-IV report the development of the HER2-specific Affibody molecule, ZHER2:342 by peptide synthesis and the use of different chelators attached to the N-terminus to allow 99mTc-labelling. Paper I described the optimisation of labelling of Affibody molecules using cysteine-based chelator sequences, in which the direct labelling method under alkaline conditions was the most suitable one. Papers II-IV report the development and optimisation of the in vivo properties of the HER2-specific Affibody molecule for high-contrast imaging. By using an array of mercaptoacetyl-based chelators, it was found that the substitution of a single amino acid in a 60 amino acid-long Affibody molecule can dramatically change the pharmacokinetics of the tracer. Strategic approaches that utilised hydrophilic amino acids, such as serine, glutamate and lysine, changed the excretion pathway from hepatobiliary to renal excretion. Problems with the high accumulation of radioactivity in the abdomen area and restricted imaging were resolved by the use of mercaptoacetyl-triglutamyl, maEEE or mercaptoacetyl-seryl-lysyl-seryl, maSKS chelators. Paper V reports the re-engineering of the HER2-specific Affibody molecule to provide a C-terminal SECG sequence using peptide synthesis. Incorporation of this sequence provided a multifunctional platform for labelling (with technetium or trivalent radiometals) and a flexible production route (recombinant or chemical synthesis). Combination of a serine, a glutamic acid and a thiol-bearing group in the chelating sequence reduced the renal accumulation of Affibody molecules. Altogether, the in vivo efficiency of Affibody molecules to target tumours and their biodistribution properties can be improved by strategic design and suitable chemistry. Hopefully, these observations will be applicable to other small peptide and protein scaffold-based tracers.
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Liu, Chang. "Giant Molecular Shape Amphiphiles Based on Polyhedral Oligomeric Silsesquioxane: Molecular Design and “Click” Synthesis." University of Akron / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=akron1367933162.
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Vijayaraghavan, Jagamya. "MOLECULAR AND MACRO-MOLECULAR CYCLIZATION: STRUCTURE BASED DRUG DESIGN OPPORTUNITIES FOR TWO LYASE ENZYMES." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1485963601042409.
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