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Orro, Graña Adolfo. "Examination of the role of binding site water molecules in molecular recognition." Thesis, SciLifeLab Stockholm, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-200164.
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A set of algorithms were designed, implemented and evaluated in order to, first, identifyclusters of conserved waters in binding pockets, i.e. hydration sites. Then, their contributionto the free energy of binding in a ligand-protein association was quantified by calculatingtheir enthalpy and entropy. The information obtained by using these algorithms couldcontribute to the development of new drugs by generating new ligands that target specifichigh-energy, unfavorable waters. Evaluation tests show that our algorithms can indeedprovide relevant data about how hydration sites influence ligand-protein binding.
2
Homeyer, Alexander von. "A superimposition method for small ligand molecules implementation and application /." [S.l.] : [s.n.], 2007. http://deposit.ddb.de/cgi-bin/dokserv?idn=984854991.
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Charmant, Jonathan Paul Henry. "Reactivity of the #mu#3-benzyne ligand towards small organic molecules." Thesis, University of Bristol, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238905.
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Ambrosek, David Hunter. "Quantum optimal control of bond selective separation of ligands from organometallic molecules." Berlin dissertation.de, 2007. http://www.dissertation.de/buch.php3?buch=5262.
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Eremina, Nadejda. "Infrared spectroscopic studies : from small molecules to large." Doctoral thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-101077.
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Infrared light (IR) was first discovered by Friedrich Wilhelm Herschel in 1800. However, until 1940’s, molecular IR studies involved only water and small organic molecules, because of the long measurement times. Development Fourier transform infrared spectroscopy (FTIR) has minimized the time required to obtain data, making it possible to investigate bigger biological systems, e.g. proteins and nucleic acids.This thesis concentrates on the applications of different IR spectroscopic techniques to a variety of biological systems and development of new approaches to study complicated biological events. The first paper in this work concerns using so-called caged compounds to study the aggregation of Alzheimer’s Aβ-peptide which is linked to the formation of neurotoxic fibrils in the brain. By adding caged-sulfate to the Aβ samples we were able to change the pH of the sample, while recording IR data and study fibril formation in a time-resolved manner. Then we used caged–ADP to study the production of ATP and creatine, mediated by creatine kinase (CK). Using CK as a helper enzyme we studied the effects of the phosphate binding on the secondary structure of SR Ca2+ATPse and determined the structural differences between two similar states Ca2E1ADP and Ca2E1ATP. In the second part of the thesis we used ATR-FTIR spectroscopy and a specially designed dialysis setup, to develop a general method to detect ligand binding events by observing the IR absorbance changes in the water hydration shell around the molecules. The same method was used to determine the binding of DNA to the transcription factors of the E2F family. E2F proteins play main part in the gene regulatory networks that control cell development. However how they recognize their DNA-binding sites and the mechanism of binding is not well understood. By using ATR-FTIR, we observed the changes in the secondary structure of the proteins, as well as the distortions to the DNA upon E2F-DNA complex formation.<br><p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>
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Morris, Daniel L. "NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY IN THE STUDY OF PROTEIN-LIGAND INTERACTIONS." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1524681449524557.
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Sarangapani, Krishna Kumar. "Characterizing selectin-ligand bonds using atomic force microscopy (AFM)." Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/11650.
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The human body is an intricate network of many highly regulated biochemical processes and cell adhesion is one of them. Cell adhesion is mediated by specific interactions between molecules on apposing cell surfaces and is critical to many physiological and pathological processes like inflammation and cancer metastasis. During inflammation, blood-borne circulating leukocytes regularly stick to and roll on the vessel walls, which consist in part, adhesive contacts mediated by the selectin family of adhesion receptors (P-, E- and L-selectin). This is the beginning of a multi-step cascade that ultimately leads to leukocyte recruitment in areas of injury or infection.
In vivo, selectin-mediated interactions take place in a hydrodynamic milieu and hence, it becomes imperative to study these interactions under very similar conditions in vitro. The goal of this project was to characterize the kinetic and mechanical properties of selectin interactions with different physiologically relevant ligands and selectin-specific monoclonal antibodies (mAbs) under a mechanically stressful milieu, using atomic force microscopy (AFM).
Elasticity studies revealed that bulk of the complex compliance came from the selectins, with the ligands or mAbs acting as relatively stiffer components in the stretch experiments. Furthermore, molecular elasticity was inversely related to selectin length with the Consensus Repeats (CRs) behaving as Hookean springs in series. Besides, monomeric vs. dimeric interactions could be clearly distinguished from the elasticity measurements. L-selectin dissociation studies with P-selectin Glycoprotein Ligand 1 (PSGL-1) and Endoglycan revealed that catch bonds operated at low forces while slip bonds were observed at higher forces. These results were consistent with previous P-selectin studies and suggested that catch bonds could contribute to the shear threshold for L-selectin-mediated rolling By contrast, only slip bonds were observed for L-selectin-antibody interactions, suggesting that catch bonds could be a common characteristic of selectin-ligand interactions. Force History studies revealed that off-rates of L-selectin-sPSGL-1 (or 2-GSP-6) interactions were not just dependent on applied force, as has been widely accepted but in fact, depended on the entire history of force application, thus providing a new paradigm for how force could regulate bio-molecular interactions.
Characterizing selectin-ligand interactions at the molecular level, devoid of cellular contributions, is essential in understanding the role played by molecular properties in leukocyte adhesion kinetics. In this aspect, data obtained from this project will not only add to the existing body of knowledge but also provide new insights into mechanisms by which selectins initiate leukocyte adhesion in shear.
8
Renberg, Björn. "Fluorescence-based ligand assays for protein detection using affibody affinity proteins." Doctoral thesis, KTH, Skolan för bioteknologi (BIO), 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-3936.
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The detection and quantification of biomolecules, and proteins in particular, are of great interest since these molecules are of fundamental importance to our well-being. Body fluids, as for instance human blood, are well suited for sampling of protein levels. However, the complexity of the fluids and the low abundance of many of the interesting biomolecules makes detection and quantification difficult. This has spurred an interest into the development of many protein detection methods, and of these, ligand assays have proven particularly suitable. In this thesis, different types of ligand assays for protein detection have been developed using affibody molecules as ligands. In a first study, a homogeneous competitive detection assay was investigated, based on antiidiotypic affibody molecule pairs and fluorescence resonance energy transfer (FRET) as reporting system. The individual members of two anti-idiotypic affibody pairs, each consisting of a target binding (idiotypic) and an anti-idiotypic affibody ligand, were labeled with a donor fluorophore and an acceptor fluorophore, respectively. Incubation with the two target proteins IgA and Taq DNA polymerase resulted in a concentration dependent decrease in the FRET signal, allowing for target protein detection and quantification. For Taq DNA polymerase, detection in 25% human plasma was also possible in the same concentration span as in buffer. In a second study, a homogeneous, non-competitive detection system was described. Affibody molecules of 58 amino acids directed against IgA and IgG were produced with chemical synthesis, and two fluorophores capable of FRET were site-specifically introduced. Binding of target protein induced a concentration-dependent change in the relative emission of the two fluorophores, which formed the basis for the detection system. In two studies, affibody molecules were evaluated and shown to function well as capture ligands on microarrays. Synthetic affibody molecules directed against Taq DNA polymerase and IgA were modified by the introduction of immobilization tags. Specific immobilization via a C-terminal cysteine or a biotin moiety, or random immobilization via amino groups, were studied in protein microarray experiments and SPR-based biosensor studies. The experiments showed that all immobilization chemistries resulted in functional capture molecules. A short spacer was also introduced, situated between the affibody and the cysteine and biotin moieties, which was shown to improve binding for all constructs. Multidomain affibody constructs of up to four N- to C-terminally linked domains were shown to increase the amount of bound target, compared to monomeric affibody ligands. Six dimeric affibody constructs directed against IgA, IgG, IgE, Taq DNA polymerase, TNF-α and insulin, respectively, showed low limits of detections for their targets and little or no cross-reactivity with the other target proteins. Dimeric affibody molecules directed against IgA and TNF-α were also shown to function in a sandwich format with antibodies for detection of targets in buffer and in human serum and plasma. Successful discrimination between normal and IgA-deficient sera showed that affibody molecules could be used for specific detection of protein in highly complex backgrounds on microarrays.<br>QC 20100916
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Zhang, Fang. "Two-dimensional binding kinetics of intracellular adhesion molecule-1 for αL inserted domains and β₂ integrins at different conformational states". Thesis, Georgia Institute of Technology, 2004. http://hdl.handle.net/1853/9452.
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Zhang, Fang. "Two-dimensional binding kinetics of intracellular adhesion molecule-1 for [alpha]L inserted domains and [beta]₂ integrins at different conformational states." Available online, Georgia Institute of Technology, 2004:, 2004. http://etd.gatech.edu/theses/available/etd-06072004-131425/unrestricted/zhang%5Ffang%5F200405%5Fms.pdf.
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Engelhart, Aaron Edward. "Nucleic acid assembly, polymerization, and ligand binding." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/45979.
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In the past 30 years, the discovery of capabilities of nucleic acids far beyond their well-known information-bearing capacity has profoundly influenced our understanding of these polymers. The discovery by the Cech and Altman labs that nucleic acids could perform catalytic functions, coupled with the Gold and Szostak groups’ demonstration of the de novo evolution of nucleic acids that bind arbitrary ligands, has resulted in a proliferation of newfound roles for these molecules. Nucleic acids have found utility in both engineered systems, such as aptamer therapeutics, as well as in newly appreciated roles in extant organisms, such as riboswitches. As a result of these discoveries, many have pondered the potential importance of the dual (catalytic and informational) roles of nucleic acids in early evolution. A high-yielding synthetic route for the nonenzymatic polymerization of nucleic acids, based on the aqueous self-assembly of their components, would provide a powerful tool in nucleic acid chemistry, with potential utility in prebiotic and contemporary nucleic acid systems alike – however, such a route remains elusive. In this thesis, I describe several steps towards such a synthetic route. In these systems, a nucleic-acid binding ligand drives the assembly of short DNA and RNA duplexes, promoting the production of long nucleic acid polymers, while suppressing the production of short, cyclic species. Additionally, the use of a reversible covalent linkage allows for the production of long polymers, as well as the incorporation of previously cyclized products into these polymers. I also report several explorations of novel base pairings, nucleic acid-ligand interactions, and nucleic acid-ion interactions that have informed our studies of self-assembling nucleic acid systems.
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Glouchkova, Ludmila. "Biological role of the expression of tumor necrosis factor receptor ligand family molecules on acute leukemia cells." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=970363133.
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Hohenberger, Johannes [Verfasser], and Karsten [Gutachter] Meyer. "Activation of Small Molecules at Iron Complexes in Varying Trigonal Ligand Environments / Johannes Hohenberger ; Gutachter: Karsten Meyer." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2017. http://d-nb.info/1140917099/34.
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Gers-Barlag, Alexander. "Two-in-one Pincer Type Ligands and Their Metal Complexes for Catalysis." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://hdl.handle.net/11858/00-1735-0000-002B-7D45-0.
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Schafer, Jamie Lynn. "Rhesus macaque KIR recognition of MHC class I molecules: Ligand identification and modulation of interaction by SIV peptides." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11683.
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Natural killer (NK) cells can kill virus-infected cells without prior antigenic exposure, and are therefore important for controlling viral replication prior to the onset of adaptive immune responses. Primate NK cells express activating and inhibitory killer-cell immunoglobulin-like receptors (KIRs) that bind to specific major histocompatibility complex (MHC) class I molecules. The importance of KIR interactions with MHC class I in human immunodeficiency virus (HIV) pathogenesis is demonstrated by the association of select KIR and MHC class I genotypes with delayed progression to acquired immunodeficiency syndrome (AIDS).
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Ghiasi, Zahra. "Development of a Computational Mechanism to Generate Molecules with Drug-likeCharacteristics." Ohio University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou162861276157897.
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PALMIOLI, ALESSANDRO. "Synthesis and biological characterization of new molecules pharnacologically active derived from natural compouds." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2009. http://hdl.handle.net/10281/7461.
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The inhibition of the oncogenic variants of Ras proteins represents an interesting and promising research field for the development of new anticancer therapies. During this thesis several important data were collected in order to clarify the structure activity relationship in Ras-inhibitors. Then new lead compounds derived from natural carbohydrates were designed and synthesized following a rational drug design approach. These original water-soluble molecules were investigated for the biological activity point of view; in addition the binding to human Ras was fully investigated, identifying the ligand-Ras binding interface.
18
Jaquillard, Lucie. "Spectrométrie de masse supramoléculaire : caractérisation de l'intéraction non-covalente entre PEBP1/RKIP humaine et des analogues de nucléotides." Phd thesis, Université d'Orléans, 2012. http://tel.archives-ouvertes.fr/tel-00923153.
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L'étude des interactions non-covalentes et des relations structure-fonction est à la base de la compréhension des systèmes biologiques. La MS supramoléculaire est une technique de choix pour l'étude des interactions protéine/protéine ou protéine/ligand. Dans le cadre d'études qualitatives ou quantitatives, pour chaque système étudié, les conditions expérimentales et les paramètres instrumentaux ont été optimisés pour conserver le complexe en phase gazeuse (1). L'objectif principal de ce travail est de caractériser le site nucléotidique de hPEBP1 et de contribuer à la découverte de molécules anti-métastases. Sur le plan fonctionnel, une activité enzymatique de hPEBP1 n'a pas pu être mise en évidence. Pour ce projet, une méthode MS de détermination de KD de complexes à faible affinité, plus précise et ne nécessitant par l'utilisation d'un ligand de référence a été développée (2). Une recherche des déterminants structuraux d'un ligand optimal de hPEBP1 a été réalisée par criblage de composés issus d'une synthèse raisonnée basée sur la structure des nucléotides FMN et GTP et par la détermination de leur KD (3). Les criblages ont montré que les critères structuraux indispensables pour la liaison sont la présence d'un groupement chargé ou donneur d'électrons, d'une structure apparentée à une base azotée et d'un cycle additionnel. Une part importante de l'affinité est liée au caractère hydrophobe du ligand. Certains ligands de synthèse ont montré une activité inhibitrice de l'invasion des lignées tumorales.
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Betz, Michael [Verfasser], and Gerhard [Akademischer Betreuer] Klebe. "Development of models to describe the dynamics and interaction with water molecules in protein-ligand binding / Michael Betz. Betreuer: Gerhard Klebe." Marburg : Philipps-Universität Marburg, 2015. http://d-nb.info/1081215569/34.
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Marot, Christophe. "Conception de nouvelles molecules a activite serotoninergique par des methodes qsar et des etudes de dynamique moleculaire de complexes ligand/recepteur." Orléans, 1995. http://www.theses.fr/1995ORLE2073.
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Desireux de mettre au point de nouvelles substances pouvant presenter une activite biologique potentielle au niveau du systeme nerveux central, nous avons envisage d'etudier les relations quantitatives structure-activite (qsar) sur plusieurs familles de composes 5-ht#1#a. L'objectif etait de predire l'activite et la selectivite biologique de nouveaux ligands 5-ht#1#a vis-a-vis de certains neurorecepteurs transmembranaires (5-ht#1#a, #1, #2, d#2). Pour ce faire, 382 composes issus de differentes familles chimiques (indole, tetraline, chromane, thiochromane, piperazine, etc. . . ) ont ete modelises et superposes aux pharmacophores 5-ht#1#a. Nous avons ensuite, pour chaque molecule, calcule et compare differents descripteurs moleculaires representatifs de l'aspect electrostatique, lipophilique, sterique et topologique. Les differentes tables constituees des composes et des descripteurs ont ensuite ete etudiees par des analyses statistiques comme l'analyse en composantes principales, l'analyse discriminante, la regression multiple et l'analyse partial least square. A partir des meilleurs modeles statistiques, l'activite biologique de nouveaux ligands a ete predite. Apres la synthese et les tests pharmacologiques, ces predictions se sont revelees precises (ecart moyen de 1 unite de pic#5#0). En parallele, une etude de dynamique moleculaire du recepteur serotoninergique transmembranaire 5-ht#1#a a ete entreprise afin de rendre compte de l'importance fonctionnelle de ces ligands au niveau des interactions electrostatiques, steriques et lipophiliques mises en jeu au sein du site actif du recepteur. Ces etudes sur un nombre limite de complexes ligand/recepteur ont aussi ete menees afin de comprendre le role de certaines parties fonctionnelles de ces ligands, role mal defini jusqu'alors par les autres techniques. Nous avons aussi obtenu des informations qualitatives sur les interactions et la mobilite de certaines parties du recepteur, entre autres sur les helices transmembranaires tmh5, 6 et 7
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Berg, Lotta. "Exploring non-covalent interactions between drug-like molecules and the protein acetylcholinesterase." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-129900.
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The majority of drugs are small organic molecules, so-called ligands, that influence biochemical processes by interacting with proteins. The understanding of how and why they interact and form complexes is therefore a key component for elucidating the mechanism of action of drugs. The research presented in this thesis is based on studies of acetylcholinesterase (AChE). AChE is an essential enzyme with the important function of terminating neurotransmission at cholinergic synapses. AChE is also the target of a range of biologically active molecules including drugs, pesticides, and poisons. Due to the molecular and the functional characteristics of the enzyme, it offers both challenges and possibilities for investigating protein-ligand interactions. In the thesis, complexes between AChE and drug-like ligands have been studied in detail by a combination of experimental techniques and theoretical methods. The studies provided insight into the non-covalent interactions formed between AChE and ligands, where non-classical CH∙∙∙Y hydrogen bonds (Y = O or arene) were found to be common and important. The non-classical hydrogen bonds were characterized by density functional theory calculations that revealed features that may provide unexplored possibilities in for example structure-based design. Moreover, the study of two enantiomeric inhibitors of AChE provided important insight into the structural basis of enthalpy-entropy compensation. As part of the research, available computational methods have been evaluated and new approaches have been developed. This resulted in a methodology that allowed detailed analysis of the AChE-ligand complexes. Moreover, the methodology also proved to be a useful tool in the refinement of X-ray crystallographic data. This was demonstrated by the determination of a prereaction conformation of the complex between the nerve-agent antidote HI-6 and AChE inhibited by the nerve agent sarin. The structure of the ternary complex constitutes an important contribution of relevance for the design of new and improved drugs for treatment of nerve-agent poisoning. The research presented in the thesis has contributed to the knowledge of AChE and also has implications for drug discovery and the understanding of biochemical processes in general.
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BRUNIQUEL, DENIS. "Regulation de l'expression genique de lag-3 (lymphocyte activation gene-3), un ligand des molecules du complexe majeur d'histocompatibilite de classe ii." Paris 7, 1997. http://www.theses.fr/1997PA077184.
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Le gene lag-3 code pour une proteine membranaire exprimee uniquement a la surface des lymphocytes t et nk actives chez l'homme. Ce gene presente des similarites de sequence avec cd4 ainsi qu'une meme localisation genomique, suggerant l'existence d'un ancetre phylogenetique commun pour lag-3 et cd4. Par ailleurs, il a ete montre que lag-3 et cd4 partageaient egalement le meme ligand : les molecules du complexe majeur d'histocompatibilite de classe ii. Le fait que lag-3 soit un antigene d'activation dont l'expression est specifique de certaines lignees cellulaires, contrairement a cd4 exprime egalement sur des lymphocytes au repos, des macrophages, des eosinophiles, nous fait penser que l'activite de son promoteur est fortement regulee. Au cours de cette etude, nous avons etudie la regulation transcriptionnelle de lag-3. La premiere approche a consiste a etudier le locus lag-3 et de determiner l'environnement de ce gene. Nous avons pu mettre en evidence la presence de plusieurs genes, la parathymosine ou le gene cd4 a proximite de lag-3. Une etude plus systematique nous a permis de mettre en evidence les differents elements necessaires a la transcription de lag-3. Nous avons identifie plusieurs sites d'initiation de la transcription de lag-3 sur des lymphocytes t actives. L'analyse des sites d'hypersensibilites a l'adnase i a permis de localiser les principaux elements regulateurs. Nous avons identifie une region activatrice, capable de fixer des facteurs de transcription tel que nf-kappab ou nfat. Par ailleurs, nous avons localise plusieurs regions capables d'inhiber l'activite du promoteur minimal, ou celle de l'enhancer de lag-3. Ainsi, nous avons montre que la restriction de l'expression de lag-3 aux lymphocytes t actives etait, due a une regulation au niveau de la transcription du gene. Enfin, nous avons determine que l'expression de la molecule lag-3 a la surface des cellules humaines t activees etait modulee par certaines cytokines comme l'il-2, l'il-7 ou l'il-12. En conclusion, ce travail constitue une etude preliminaire de la regulation de lag-3. La comprehension des mecanismes moleculaires regulant l'expression de lag-3 au cours des phenomenes d'activation et/ou de differenciation cellulaire pourrait permettre de mieux comprendre a terme le role de cette molecule.
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Cisek, Katryna. "Rational Optimization of Small Molecules for Alzheimer’s Disease Premortem Diagnosis." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338325484.
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Loukova, G. V., V. V. Vasiliev, V. L. Ivanov, M. Ya Melnikov, V. A. Smirnov, and E. E. Melnichuk. "Two−photon Processes in Organometallic Molecules and Clusters: T−T Absorption of Group IV Metal Complexes." Thesis, Sumy State University, 2013. http://essuir.sumdu.edu.ua/handle/123456789/35395.
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Triplet – triplet absorption of d0 metal complexes was for the first time revealed and studied by means of pulse photolysis and electron-exchange (Dexter) resonant energy transfer energy transfer.
When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/35395
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Bruce, Macdonald Hannah. "The role of water in drug binding : calculating positions and binding free energies of active site water molecules, and their influence on ligand binding." Thesis, University of Southampton, 2018. https://eprints.soton.ac.uk/428052/.
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This thesis studies the ability of computer simulation to determine the location and free energy of binding of active site water molecules, and the energetic effect water molecules can have on ligand binding. The primary method used involves sampling within the grand canonical ensemble, using grand canonical Monte Carlo (GCMC). The first results chapter looks at the introduction of replica exchange (RE) to GCMC simulations, and the improvements this yields in the reliability of calculated water binding free energies. The results show that GCMC can determine water binding free energies that are consistent with double-decoupling methods, while being able to calculate multiple water free energies simultaneously, without a priori knowledge of water locations. The second chapter explores the accuracy of GCMC at determining the locations of active site water molecules, using a large dataset of molecules and targets of pharmaceutical interest. Understanding the accuracy of GCMC to reproduce crystallographic water locations allows for reliable calculation of protein-ligand complexes without experimentally known water locations being known. Focus will be placed on the variation of quoted water placement success rates with different published protocols. The final chapter of this thesis involves the integration of two techniques; GCMC and ligand alchemical perturbation simulations. Grand canonical Alchemical Perturbations (GCAP) will be presented, whereby relative binding free energies of pairs of ligands are calculated, while active site water molecules are sampled using the grand canonical ensemble. This GC sampling of water allows the ligands water network to dynamically adapt. GCAP will be demonstrated for two example systems, where active site water molecules are a key factor in the ligand binding affinities.
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CHHABRA, MONICA. "Modeling and Analysis of Ligand Docking to Norovirus Capsid Protein for the Computer-Aided Drug Design." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1209001634.
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LA, MONICA Gabriele. "Correlation between cell line chemosensitivity and protein expression pattern as new approach for the design of targeted anticancer small molecules." Doctoral thesis, Università degli Studi di Palermo, 2022. https://hdl.handle.net/10447/573085.
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BACKGROUND AND RATIONALE: Over the past few decades, several databases with a significant amount of biological data related to cancer cells and anticancer agents (e.g.: National Cancer Institute database, NCI; Cancer Cell Line Encyclopedia, CCLE; Genomic and Drug Sensitivity in Cancer portal, GDSC) have been developed. The huge amount of heterogeneous biological data extractable from these databanks (among all, drug response and protein expression) provides a real foundation for predictive cancer chemogenomics, which aims to investigate the relationships between genomic traits and the response of cancer cells to drug treatment with the aim to identify novel therapeutic molecules and targets. In very recent times many computational and statistical approaches have been proposed to integrate and correlate these heterogeneous biological data sequences (protein expression – drug response), with the aim to assign the putative mechanism of action of anticancer small molecules with unknown biological target/s. The main limitation of all these computational methods is the need for experimental drug response data (after screening data). From this point of view, the possibility to predict in silico the antiproliferative activity of new/untested small molecules against specific cell lines, could enable correlations to be found between the predicted drug response and protein expression of the desired target from the very earliest stages of research. Such an innovative approach could allow to select the compounds with molecular mechanisms that are more likely to be connected with the target of interest preliminary to the in vitro assays, which would be a critical aid in the design of new targeted anticancer agents.
RESULTS: In the present study, we aimed to develop a new innovative computational protocol based on the correlation of drug activity and protein expression data to support the discovery of new targeted anticancer agents. Compared with the approaches reported in the literature, the main novelty of the proposed protocol was represented by the use of predicted antiproliferative activity data, instead of experimental ones. To this aim, in the first phase of the research the new in silico Antiproliferative Activity Predictor (AAP) tool able to predict the anticancer activity (expressed as GI50) of new/untested small molecules against the NCI-60 panel was developed. The ligand-based tool, which took the advantages of the consolidated expertise of the research group in the manipulation of molecular descriptors, was adequately validated and the reliability of the prediction was further confirmed by the analysis of an in-house database and subsequent evaluation of a set of molecules selected by the NCI for the one-dose/five-doses antiproliferative assays.
In the second part of the study, a new computational method to correlate drug activity data and protein expression pattern data was proposed and evaluated by analysing several case studies of targeted drugs tested by NCI, confirming the reliability of the proposed method for the biological data analysis.
In the last part of the project the proposed correlation approach was applied to design new small molecules as selective inhibitors of Cdc25 phosphatase, a well-known protein involved in carcinogenic processes. By means of this innovative approach, integrated with other classical ligand/structures-based techniques, it was possible to screen a large database of molecular structures, and to select the ones with optimal relationship with the focused target. In vitro antiproliferative and enzymatic inhibition assays of the selected compounds led to the identification of new structurally heterogeneous inhibitors of Cdc25 proteins and confirmed the results of the in silico analysis.
CONCLUSIONS: Collectively, the obtained results showed that the correlation between protein expression pattern and chemosensitivity is an innovative, alternative, and effective method to identify new modulators for the selected targets. In contrast to traditional in silico methods, the proposed protocol allows for the selection of molecular structures with heterogeneous scaffolds, which are not strictly related to the binding sites and with chemical-physical features that may be more suitable for all the pathways involved in the overall mechanism. The biological assays further corroborate the robustness and the reliability of this new approach and encourage its application in the anticancer targeted drug discovery field.
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Panei, Francesco Paolo. "Advanced computational techniques to aid the rational design of small molecules targeting RNA." Electronic Thesis or Diss., Sorbonne université, 2024. http://www.theses.fr/2024SORUS106.
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Les molécules d'ARN sont devenues des cibles thérapeutiques majeures, et le ciblage par petites molécules se révèle particulièrement prometteur. Cependant, malgré leur potentiel, le domaine est encore en développement, avec un nombre limité de médicaments spécifiquement conçus pour l'ARN. La flexibilité intrinsèque de l'ARN, bien qu'elle constitue un obstacle, introduit des opportunités thérapeutiques que les outils computationnels actuels ne parviennent pas pleinement à exploiter malgré leur prédisposition. Le projet de cette thèse est de construire un cadre computationnel plus complet pour la conception rationnelle de composés ciblant l'ARN. La première étape pour toute approche structure-based est l'analyse des connaissances structurales disponibles. Cependant, il manquait une base de données complète, organisée et régulièrement mise à jour pour la communauté scientifique. Pour combler cette lacune, j'ai créé HARIBOSS, une base de données de toutes les structures expérimentalement déterminées des complexes ARN-petites molécules extraites de la base de données PDB. Chaque entrée de HARIBOSS, accessible via une interface web dédiée (https://hariboss.pasteur.cloud), est annotée avec les propriétés physico-chimiques des ligands et des poches d'ARN. Cette base de données constamment mise à jour facilitera l'exploration des composés drug-like liées à l'ARN, l'analyse des propriétés des ligands et des poches, et en fin de compte, le développement de stratégies in silico pour identifier des petites molécules ciblant l'ARN. Lors de sa sortie, il a été possible de souligner que la majorité des poches de liaison à l'ARN ne conviennent pas aux interactions avec des molécules drug-like. Cela est dû à une hydrophobicité moindre et une exposition au solvant accrue par rapport aux sites de liaison des protéines. Cependant, cela résulte d'une représentation statique de l'ARN, qui peut ne pas capturer pleinement les mécanismes d'interaction avec de petites molécules. Il était nécessaire d'introduire des techniques computationnelles avancées pour une prise en compte efficace de la flexibilité de l'ARN. Dans cette direction, j'ai mis en œuvre SHAMAN, une technique computationnelle pour identifier les sites de liaison potentiels des petites molécules dans les ensembles structuraux d'ARN. SHAMAN permet d'explorer le paysage conformationnel de l'ARN cible par des simulations de dynamique moléculaire atomistique. Dans le même temps, il identifie efficacement les poches d'ARN en utilisant de petits fragments dont l'exploration de la surface de l'ARN est accélérée par des techniques d'enhanced sampling. Dans un ensemble de données comprenant divers riboswitches structurés ainsi que de petits ARN viraux flexibles, SHAMAN a précisément localisé des poches résolues expérimentalement, les classant les régions d’interaction préférées. Notamment, la précision de SHAMAN est supérieure à celle d'autres outils travaillant sur des structures statiques d'ARN dans un scénario réaliste de découverte de médicaments où seules les structures apo de la cible sont disponibles. Cela confirme que SHAMAN est une plateforme robuste pour les futures initiatives de conception de médicaments ciblant l'ARN avec de petites molécules, en particulier compte tenu de sa pertinence potentielle dans les campagnes de criblage virtuel. Dans l'ensemble, ma recherche contribue à améliorer notre compréhension et notre utilisation de l'ARN en tant que cible pour les médicaments à petites molécules, ouvrant la voie à des stratégies thérapeutiques plus efficaces dans ce domaine en évolution<br>RNA molecules have recently gained huge relevance as therapeutic targets. The direct targeting of RNA with small molecule drugs emerges for its wide applicability to different classes of RNAs. Despite this potential, the field is still in its infancy and the number of available RNA-targeted drugs remains limited. A major challenge is constituted by the highly flexible and elusive nature of the RNA targets. Nonetheless, RNA flexibility also presents unique opportunities that could be leveraged to enhance the efficacy and selectivity of newly designed therapeutic agents. To this end, computer-aided drug design techniques emerge as a natural and comprehensive approach. However, existing tools do not fully account for the flexibility of the RNA. The project of this PhD work aims to build a computational framework toward the rational design of compounds targeting RNA. The first essential step for any structure-based approach is the analysis of the available structural knowledge. However, a comprehensive, curated, and regularly updated repository for the scientific community was lacking. To fill this gap, I curated the creation of HARIBOSS ("Harnessing RIBOnucleic acid - Small molecule Structures"), a database of all the experimentally-determined structures of RNA-small molecule complexes retrieved from the PDB database. HARIBOSS is available via a dedicated web interface (https://hariboss.pasteur.cloud), and is regularly updated with all the structures resolved by X-ray, NMR, and cryo-EM, in which ligands with drug-like properties interact with RNA molecules. Each HARIBOSS entry is annotated with physico-chemical properties of ligands and RNA pockets. HARIBOSS repository, constantly updated, will facilitate the exploration of drug-like compounds known to bind RNA, the analysis of ligands and pockets properties and, ultimately, the development of in silico strategies to identify RNA-targeting small molecules. In coincidence of its release, it was possible to highlight that the majority of RNA binding pockets are unsuitable for interactions with drug-like molecules, attributed to the lower hydrophobicity and increased solvent exposure compared to protein binding sites. However, this emerges from a static depiction of RNA, which may not fully capture their interaction mechanisms with small molecules. In a broader perspective, it was necessary to introduce more advanced computational techniques for an effective accounting of RNA flexibility in the characterization of potential binding sites. In this direction, I implemented SHAMAN, a computational technique to identify potential small-molecule binding sites in RNA structural ensembles. SHAMAN enables the exploration of the target RNA conformational landscape through atomistic molecular dynamics. Simultaneously, it efficiently identifies RNA pockets using small probe compounds whose exploration of the RNA surface is accelerated by enhanced-sampling techniques. In a benchmark encompassing diverse large, structured riboswitches as well as small, flexible viral RNAs, SHAMAN accurately located experimentally resolved pockets, ranking them as preferred probe hotspots. Notably, SHAMAN accuracy was superior to other tools working on static RNA structures in the realistic drug discovery scenario where only apo structures of the target are available. This establishes SHAMAN as a robust platform for future drug design endeavors targeting RNA with small molecules, especially considering its potential applicability in virtual screening campaigns. Overall, my research contributed to enhance our understanding and utilization of RNA as a target for small molecule drugs, paving the way for more effective drug design strategies in this evolving field
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SHIVAKUMAR, YOGESH. "Development of novel approaches to modulate the immune response. Analysis of the effects of triggering the ICOS ligand and use of biocompatible/biodegradable nano/micro particles loaded with immunomodulatory molecules." Doctoral thesis, Università del Piemonte Orientale, 2015. http://hdl.handle.net/11579/115576.
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Anupam, Rajaneesh. "Characterization of binding of tRNA and ligands to T box antiterminator." View abstract, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3282047.
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Schechner-Resom, Martina Gabriele. "Ligand binding and molecular flexibility : Studies on DNA gyrase B." Université Louis Pasteur (Strasbourg) (1971-2008), 2005. http://www.theses.fr/2005STR1A001.
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L’ADN gyrase est une enzyme vitale pour la bactérie grâce à sa capacité de manipuler les molécules d’ADN dans la cellule vivante. Cette capacité fait de l’ADN gyrase une cible idéale pour des composés anti-infectieux. Dans ce travail, l’ADN gyrase a été étudié par des méthodes de modélisatoin moléculaire. Une approche de conception de ligands basée sur la structure a été entreprise sur le sous-domaine N-terminal de 24 kDa de l’ADN gyrase B (domaine GHKL). La flexibilité de deux boucles du site actif du domaine GHKL a été étudiée par des simulations de dynamiques moléculaires en présence de différents ligands. Dans une dernière partie, une analyse des modes normaux du dimère du domaine N-terminal de 43 kDa a été entreprise<br>DNA gyrase is a vital bacterial enzyme necessary for the handling of the large DNA molecules in the living cell. Therefore DNA gyrase is an ideal target enzyme for anti-infectious compounds. In this work DNA gyrase has been studied by molecular modelling methods. A computational structure-based ligand design approach has been carried out on the N-terminal 24 kDa subdomain of DNA gyrase B (GHKL domain). To further examine the flexibility of two active site loops, molecular dynamics simulations have been carried out on the GHKL domain in different ligand binding conditions. In a final part, normal mode analysis has been carried out on the dimer of the 43 kDa domain of DNA gyrase B
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McGregor, Lynn Marie. "Methods for the Identification of Ligand-Target Pairs from Combined Libraries of Targes and Ligands." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11370.
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Advances in genome and proteome research have led to a dramatic increase in the number of macromolecular targets of interest to the life sciences. A solution-phase method to simultaneously reveal all ligand-target binding pairs from a single solution containing libraries of ligands and targets could significantly increase the efficiency and effectiveness of target-oriented screening efforts. Here, we describe interaction-dependent PCR (IDPCR), a solution-phase method to identify binding partners from combined libraries of small-molecule ligands and targets in a single experiment. Binding between DNA-linked targets and DNA-linked ligands induces formation of an extendable duplex. Extension links codes identifying the ligand and target into one selectively amplifiable DNA molecule. In a model selection, IDPCR resulted in the enrichment of DNA encoding all five known protein-ligand pairs out of 67,599 possible sequences.
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Alnagi, Omar. "Reaction de la trimethylphosphine sur les sels de cobalt (ii) : synthese des complexes pentacoordonnes cox::(2)(pme::(3))::(3) (x=c1**(-), br**(-), i**(-), ncs**(-), no::(2)**(-)), reactivite vis-a-vis de petites molecules co, no et o::(2)." Toulouse 3, 1987. http://www.theses.fr/1987TOU30048.
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Synthese et etude physicochimique des complexes. Reactivite. Etude cristallographique de la structure indiquant une geometrie de bipyramide trigonale deformee quand x**(-)=cl**(-),br**(-),i**(-),ncs**(-) et une geometrie de pyramide a base carree pour x=no::(2)**(-). Etude des substitutions par co,no et o::(2)
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Steen, Robert. "Molecular Electronic Devices based on Ru(II) Thiophenyl Pyridine and Thienopyridine Architecture." Doctoral thesis, Mälardalens högskola, Akademin för hållbar samhälls- och teknikutveckling, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-10084.
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According to the famous axiom known as Moore’s Law the number of transistors that can be etched on a given piece of ultra-pure silicon, and therefore the computing power, will double every 18 to 24 months. However, around 2020 hardware manufacturers will have reached the physical limits of silicon. A proposed solution to this dilemma is molecular electronics. Within this field researchers are attempting to develop individual organic molecules and metal complexes that can act as molecular equivalents of electronic components such as wires, diodes, transistors and capacitors. In this work we have synthesized a number of new bi- and terdentate thiophenyl pyridine and pyridyl thienopyridine ligands and compared the electrochemical, structural and photophysical properties of their corresponding Ru(II) complexes with Ru(II) complexes of a variety of ligands based on 6-thiophen-2-yl-2,2'-bipyridine and 4-thiophen-2-yl-2,2'-bipyridine motifs. While the electrochemistry of the Ru(II) complexes were similar to that of unsubstituted [Ru(bpy)3]2+ and [Ru(tpy)2]2+, substantial differences in luminescence lifetimes were found. Our findings show that, due to steric interactions with the auxiliary bipyridyl ligands, luminescence is quenched in Ru(II) complexes that incorporate the 6-thiophen-2-yl-2,2'-bipyridine motif, while it was comparable with the luminescence of [Ru(bpy)3]2+ in the Ru(II) complexes of bidentate pyridyl thienopyridine ligands. The luminescence of the Ru(II) complexes based on the 4-thiophen-2-yl-2,2'-bipyridine motif was enhanced compared to [Ru(bpy)3]2+ which indicates that complexes of this category may be applicable for energy/electron-transfer systems. At the core of molecular electronics is the search for molecular ON/OFF switches. Based on the ability of the ligand 6-thiophen-2-yl-2,2'-bipyridine to switch reversibly between cyclometallated and non-cyclometallated modes when complexed with Ru(tpy) we have synthesized a number of complexes, among them a bis-cyclometallated switch based on the ligand 3,8-bis-(6-thiophen-2-yl-pyridin-2-yl)-[4,7]phenanthroline, and examined their electrochemical properties. Only very weak electronic coupling could be detected, suggesting only little, if any, interaction between the ruthenium cores.
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Pathirana, Hema M. K. K. "Ligand chemistry of tellurium." Thesis, Aston University, 1985. http://publications.aston.ac.uk/14516/.
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Rohatgi, Priyanka. "Engineering Protein Molecular Switches To Regulate Gene Expression with Small Molecules." Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/19852.
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Small molecule dependent molecular switches that control gene expression are important tool in understanding biological cellular processes and for regulating gene therapy. Nuclear receptors are ligand activated transcription factors that have been engineered to selectively respond to synthetic ligands and used as regulators of gene expression. In this work the retinoid X receptor (RXR), has been used to develop an inducible molecular switch with a near drug like compound LG335. Three RXR variants (Q275C; I310M; F313I), (I268A; I310A; F313A; L436F), (I268V; A272V; I310M; F313S; L436M) were created via site-directed mutagenesis and a structure based approach, such that they preferentially bind to the synthetic ligand LG335 and not its natural ligand, 9-cis retinoic acid. These variants show reverse ligand specificity as designed and have an EC50 for LG335 of 80 nM, 30 nM, 180 nM, respectively. The ligand binding domains of the RXR variants were fused to a yeast transcription factor Gal4 DNA binding domain. This modified chimeric fusion protein showed reverse response element specificity as designed and recognized the Gal4 response element instead of the RXR response element. The modified RXR protein did not heterodimerize with wild type RXR or with other nuclear receptor such as retinoic acid receptor. These RXR-based molecular switches were tested in retroviral vectors using firefly luciferase and green fluorescence protein and they maintain their inducible behavior with LG335. These experiments demonstrate the orthogonality of RXR variants and their possible use in regulating gene therapy.
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Urig, Christina S. "EVALUATION OF SINGLE MOLECULE DIODES FABRICATED VIA ELECTRON-BEAM LITHOGRAPHY AND METAL-ORGANIC FRAMEWORKS INCORPORATING TWO NOVEL LIGANDS, A TRIGONAL PLANAR CARBOXYLATE LIGAND AND A TETRAHEDRAL TETRAZOLATE-BASED LIGAND." Miami University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=miami1176829199.
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Hussain, Abrar. "Molecular modelling of protein-ligand interactions." Thesis, University of Nottingham, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.587840.
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In this thesis we discuss the role played by computational methods in drug discovery and present studies chiefly using molecular simulation methodologies to characterise the binding of compounds that may serve as leads for antitumour agents against two separate proteins. We report flexible docking and QSAR studies on aplyronine A, and its analogues, a potent inhibitor of the actin protein system. Our findings delineate the mechanism by which the compounds bind to an actin monomer and highlight key features of the compounds that are fundamental for actin- depolymerisation, which instigates the necessary cytotoxic response. We show that the docking energy scores for the compounds are highly correlated with experimental depolymerisation data. The results are relevant for the design of a putative set of analogues and the development of efficacious actin-targeting cancer drugs. In a second study, we focus on the ETS domain of the Elk-l transcription factor, which is key to the protein's stability and a potential target for therapeutic compounds. The work presented identifies peptide binders of the ETS domain that may be used to inform the design of peptidomimetic compounds. Using MD simulations we show the domain undergoes conformational reorganisation at the α Iβ 1 loop. By taking frames from the MD trajectory of the loop region, we conducted virtual screening experiments for libraries of all possible di- and tri-peptides against each frame. The di- peptides showed no particular preference towards the binding site. However, several tri-peptides made specific interactions with key residues involved in Elk-l dimerisation. Further, we performed peptide-bound dynamics and relative binding free energy simulations to assess the stability of each complex, and to rank more accurately the best binding peptides identified from the docking calculations. We proposed a series of peptide binders for synthesis and experimental binding studies. The thesis ends with a brief discussion on some of the limitations to, and recent advancements in the field of computational modelling, particularly in the realm of atomistic simulations for computer-aided drug discovery.
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Parker, Matthew W. "Molecular Mechanisms of Neuropilin-Ligand Binding." UKnowledge, 2014. http://uknowledge.uky.edu/biochem_etds/15.
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Neuropilin (Nrp) is an essential cell surface receptor with dual functionality in the cardiovascular and nervous systems. The first identified Nrp-ligand family was the Semaphorin-3 (Sema3) family of axon repulsion molecules. Subsequently, Nrp was found to serve as a receptor for the vascular endothelial growth factor (VEGF) family of pro-angiogenic cytokines. In addition to its physiological role, VEGF signaling via Nrp directly contributes to cancer stemness, growth, and metastasis. Thus, the Nrp/VEGF signaling axis is a promising anti-cancer therapeutic target. Interestingly, it has recently been shown that Sema3 and VEGF are functionally opposed to one another, with Sema3 possessing potent endogenous anti-angiogenic activity and VEGF serving as an attractive cue for neuronal axons. We hypothesized that direct competition for an overlapping binding site within the Nrp extracellular domain may explain the observed functional competition between VEGF and Sema3. To test this hypothesis we have separately investigated the mechanisms of VEGF and Sema3 binding to Nrp. Utilizing structural biology coupled with biophysics and biochemistry we have identified both distinct and common mechanisms that facilitate the interaction between Nrp and these two ligand families. Specifically, we have identified an Nrp binding pocket to which these ligands competitively bind. The Sema3 family uniquely requires proteolytic activation in order to engage this overlapping binding site. These findings provide critical mechanistic insight into VEGF and Sema3 mediated physiology. Additionally, these data have informed the development of small molecules, peptides, and soluble receptor fragments that function as potent and selective inhibitors of VEGF/Nrp binding with exciting therapeutic potential for treating cancer.
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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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Kingston, Justine E. "Redox-active host molecules for anion recognition." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320669.
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Lo, schiavo Valentina. "Control of ligand-receptor interaction by tuning molecular environment." Thesis, Aix-Marseille 2, 2011. http://www.theses.fr/2011AIX22109.
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L'adhésion cellulaire est un processus biologique fondamental contrôlé par des liaisons moléculaires spécifiques entre ligands et récepteurs attachés à des surfaces. La formation et la rupture de ces liens dépendent de facteurs cinétiques, mécaniques et structurelles. Le but de ce travail était d'observer comment l'interaction ICAM-1 - anti ICAM-1 pouvait être modifié en jouant i) sur la multivalence de molécules impliquées dans la liaison ii) sur la topographie de surface et iii) sur la mobilité des ligands. A cette fin, on a principalement utilisé une chambre à flux laminaire, complété par une détection de molécule unique par fluorescence.L'étude sur les effets de multivalence, utilisant des monomères et dimères d'ICAM-1, a été réalisée en absence et en présence d'une force mécanique, montrant la plus grande stabilité des liaisons divalentes. En outre, un renforcement avec la force et le temps a été trouvé et décrit avec une fonction à deux paramètres, montrant, pour les liaisons divalentes, un comportement intermédiaire entre rupture parallèles et successives des liaisons. La fréquence d'adhésion des liaisons monovalentes et bivalentes présente différentes valeurs causées par la différence de longueur de ces molécules.Les expériences d'adhésions ont été effectuées en variant la topographie du substrat pour les molécules étudiées. Une comparaison des cinétiques de liaisons sur ces surfaces ne montrent pas de différences soit dans la formation ou dans la rupture. Pour interpréter ces résultats, un modèle qui prend en compte la zone de contact réel devrait être construit à partir des images AFM des échantillons.Dans l'écoulement, le temps de contact entre les molécules est contrôlé par la convection de microsphères. Des résultats récents montrent qu'un minimum de temps est requis pour former la liaison (Robert et al. 2011). Pour tester cette prédiction, les ligands sont ancrés à une bicouche lipidique (SLB) pour étudier comment la diffusion peut modifier l'adhésion. Expérimentalement, les fréquences d'adhésion des liaisons ont montré un comportement similaire pour les SLB fixes et fluides. Toutefois, la simulation numérique prédit un effet sur la formation de la liaison, même lorsque la diffusion des ligands est faible. Il semblerait que la diffusion joue un rôle dans la dissociation de la liaison, réduisant fortement la valeur de koff pour une bicouche fluide. Cet effet peut être expliqué par la présence éventuelle de liaisons multiples dues à l'accumulation des ligands sur la surface de contact<br>Cell adhesion is a fundamental biological process mediated by specific molecular bonds formed by ligands and receptors attached to surfaces. Formation and rupture of these bonds depend on kinetic, mechanical and structural factors. The goal of this work was to observe how the ICAM-1 – anti ICAM-1 interaction can be modified by playing i) on the multivalency of molecules involved in the bond ii) on the topography of surface and iii) on the mobility of ligands. The main technique used for this purpose was the laminar flow chamber, completed by single-particle tracking in fluorescence.The study on multivalency effects, using monomeric and dimeric ICAM-1, was performed in absence and presence of mechanical force, showing the higher stability of divalent bonds. Also, a force- and time- strengthening dependence was found and described with a two-parameter function, showing, for divalent bonds, an intermediate behaviour between parallel and subsequent rupture of bonds. The adhesion frequency of monovalent and divalent bonds exhibit different values accounted by difference in length of these molecules.Adhesion experiments were performed varying the topography of the substrate for the investigated molecules. A comparison of bond kinetics on these surfaces did not show differences either in attachment or in rupture. To interpret these results, a model which takes into account the real contact area should be built from the AFM images of the samples.In the flow, the contact time between molecules is controlled by convection of microspheres. Recent results show that there is a minimal time required to form the bond (Robert et al. 2011). To test this prediction, ligands were anchored to supported lipid bilayer (SLB) to investigate how the diffusion can modify the adhesion. Experimentally, the adhesion frequencies of the bonds showed similar behaviour for fixed and fluid SLB. While, numerical simulation predicted an effect on bond formation even at low ligand diffusion. The diffusion seemed to play a role in bond dissociation, strongly reducing the value of koff for fluid bilayer. This effect can be explained by the possible presence of multiple bonds due to ligand accumulation on the contact area
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Evans, P. L. "Ligand design for homogenous catalysis." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376909.
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CALLEA, LARA. "MODELING OF LIGAND-PROTEIN BINDING WITH ADVANCED MOLECULAR DYNAMICS METHODS." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/374733.
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Questa tesi è incentrata sulla modellazione del binding ligando-proteina con metodi computazionali basati sulla dinamica molecolare. La comprensione di questo processo è fondamentale per la progettazione e la scoperta di nuovi farmaci e l'uso di metodi computazionali per supportare la ricerca sperimentale in questo campo è in costante crescita. Oggi, grazie alla crescente potenza dei computer, è possibile studiare l'intero processo di binding/unbinding del ligando e ottenere stime sulle proprietà termodinamiche e cinetiche.
Alla luce di ciò, durante il mio dottorato, diversi metodi avanzati di dinamica molecolare classica (MD) sono stati impiegati e confrontati per identificare un approccio computazionale efficace per studiare i processi di binding/unbinding dei ligandi. In particolare, è stato sviluppato un protocollo basato sulla combinazione degli approcci steered MD (sMD) e Metadinamica (MetaD) con Path Collective Variables (PCVs) con lo scopo di utilizzare i vantaggi di entrambi i metodi per ottenere una descrizione completa del processo. Mentre il metodo SMD è stato impiegato per studiare diversi percorsi di disassociazione e identificare quello preferito, la MetaD con le PCVs è stato utilizzato per determinare più accuratamente l'energia libera di legame. Il protocollo proposto è stato applicato con successo per studiare il legame del ligando al fattore inducibile dell'ipossia (HIF-2α) e ha dimostrato di essere efficace per le simulazioni effettuate sia su una struttura a raggi X nota del ligando-proteina che su una posa di docking.
D'altra parte, la maggior parte dei metodi MD richiede la produzione di diverse repliche o lunghe simulazioni per campionare più volte l'evento di binding/unbinding al fine di ottenere una statistica affidabile del processo. Questo produce la necessità di metodi in grado di analizzare tutti gli eventi simulati in una sola volta e di fornire un quadro chiaramente interpretabile delle differenze nei pathway campionati. Per questo motivo, è stato sviluppato un tool basato sulle mappe auto-organizzanti (SOM). Lo strumento PathDetect-SOM (Pathway Detection on SOM), sfruttando i vantaggi dell'ordinamento topologico della SOM, permette di rappresentare visivamente i percorsi di legame campionati durante diversi eventi/repliche MD in una chiara rappresentazione bidimensionale. Inoltre, possono essere derivati suggerimenti sulle proprietà cinetiche e termodinamiche del processo. Lo strumento è stato applicato con successo a diversi casi di studio per dimostrare la sua applicabilità generale.
Inoltre, come parte di un progetto eseguito presso il centro di ricerca Jülich (Istituto di Simulazioni Avanzate e Istituto di Neuroscienze e Medicina) sotto la supervisione del Prof. Paolo Carloni, è stata testata una nuova interfaccia ibrida di meccanica quantistica/meccanica molecolare (QM/MM) (MiMiC). Il codice, che permette simulazioni di dinamica molecolare QM/MM di sistemi biomolecolari, è stato applicato alla proteina chinasi mitogeno-attivata p38 in complesso con il ligando 2g per studiare il processo di unbinding del ligando. L'attenzione si è concentrata sulla prima fase del processo che coinvolge la dinamica del ligando nel suo stato legato. Le simulazioni MD QM/MM sono state efficaci nel descrivere accuratamente le interazioni ligando-proteina. In particolare, monitorando il cambiamento delle cariche atomiche durante la simulazione e calcolando la differenza di densità elettronica tra il ligando nel suo stato legato e nel vuoto, sono stati ottenuti approfondimenti sugli effetti di polarizzazione del campo elettrico della proteina sul ligando. Ci si aspetta che questi effetti, anche se piccoli nello stato legato, diventino molto importanti nelle fasi successive del processo di unbinding.<br>This thesis focused on modeling of ligand-protein binding with computational methods based on molecular dynamics. Understanding this process is crucial for the design and discovery of new drugs and the use of computational methods to support experimental research in this field is constantly growing. Nowadays, thanks to the increasing computer power, it is possible to study the complete ligand binding/unbinding process and obtain estimate on thermodynamic and kinetic properties.
In view of this, during my PhD, different advanced classical molecular dynamics (MD) methods were employed and compared to identify an effective computational approach for studying ligand binding/unbinding processes. Specifically, a protocol based on combination of the steered MD (sMD) and the Metadynamics (MetaD) with Path Collective Variables (PCVs) approaches was developed with the aim of using the advantages of both methods to obtain a complete description of the process. While the sMD method was employed to investigate different unbinding pathways and identify the preferred one, MetaD with PCVs was used to determine more accurately the binding free energy. The proposed protocol was successfully applied to study ligand binding to the Hypoxia Inducible Factor (HIF-2α) and it demonstrated to be effective for simulations performed both on a known ligand-protein X-ray structure and on a docking pose.
On the other hand, most of the MD methods requires the production of several replicas or long simulations to sample the binding/unbinding event several times in order to obtain a reliable statistics of the process. This produces the need of methods able to analyze all the simulated events at once and to provide a clearly interpretable picture of the differences in the sampled pathways. For this reason, a tool based on the self-organizing maps (SOMs) was developed. The PathDetect-SOM (Pathway Detection on SOM) tool, exploiting the advantages of the topological ordering of the SOM, allowing to visually represent the binding paths sampled during different MD events/replicas in a clear bidimensional representation. In addition, hints on the kinetic and thermodynamic properties of the process can be derived. The tool was successfully applied to different study-cases to demonstrate its general applicability.
Furthermore, as part of a project performed at the Jülich research center (Institute of Advanced Simulations and Institute for Neuroscience and Medicine) under the supervision of Prof. Paolo Carloni, a novel hybrid quantum mechanics/molecular mechanics (QM/MM) interface (MiMiC) was tested. The code, that allows QM/MM molecular dynamics simulations of biomolecular systems, was applied to the mitogen-activated protein kinase p38 in complex with the 2g ligand to investigate the ligand unbinding process. The focus was on the first step of the process involving the dynamics of the ligand in its bound state. QM/MM MD simulations were effective in describing ligand-protein interactions accurately. In particular, by monitoring the change of the atomic charges during the simulation and calculating the electronic density difference between the ligand in its bound state and in vacuum, insights into the polarization effects of the protein electric field onto the ligand were obtained. It is expected that these effects, albeit small in the bound state, become very important in the following steps of the unbinding process.
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Cronin, Leroy. "Ligand design : new small molecule models for Carbonic Anhydrase." Thesis, University of York, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288064.
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André, Joseph. "Modélisation moléculaire de complexes Tubuline-Ligand." Thesis, Evry-Val d'Essonne, 2012. http://www.theses.fr/2011EVRY0026.
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Les microtubules sont des polymères cylindriques de tubuline-αβ, membres du cytosquelette eucaryote. Ils possèdent une dynamique intrinsèque nécessaire à de nombreuses fonctions cellulaires telle que la mitose. L’hydrolyse du nucléotide GTP dans les polymères de tubuline-αβ ainsi que les interactions entre la tubuline et les protéines partenaires ou les molécules à visées pharmacologiques, jouent un rôle critique sur la dynamique des microtubules. Durant cette thèse, des approches de modélisation moléculaire ont été utilisées pour mieux appréhender les interactions tubuline-ligand à l’échelle atomique et contribuer au développement de nouvelles molécules actives. Des simulations de dynamiques moléculaires ont été réalisées pour étudier l’effet de différents nucléotides dans la tubuline-β sur la structure et la dynamique du protofilament de tubuline. Nous proposons un rôle du résidu αE254 dans la coordination du magnésium catalytique. Nous observons également des changements conformationnels aux interfaces latérales et un réarrangement de structure aux interfaces longitudinales qui peuvent affecter la stabilisation du microtubule. Des travaux menés au laboratoire ont montré que la colchicine et le carbendazime se fixent dans des poches voisines dans la sous-unité tubuline-β et inhibent la prolifération cellulaire. Nous avons proposé un site de fixation du carbendazime dans les complexes tubuline-colchicine à l’aide de l’amarrage moléculaire et de simulations de dynamiques moléculaires. Ces expériences ont mené au design de molécules hybrides composées des noyaux colchicine et carbendazime reliés par un linker. Une de ces molécules hybrides a été synthétisée et testée avec succès sur des lignées de cellules HeLa. Enfin, nous avons construit des peptides cycliques dérivées d’I19L, un peptide anti-microtubule identifié au laboratoire. Des simulations de dynamique moléculaire et des calculs d’énergie libre de liaisons ont permis d’évaluer ces peptides. Enfin, des mutations ont été proposées afin d’optimiser l’interaction entre le meilleur peptide et la tubuline<br>Microtubules are cylindrical polymers of αβ-tubulin heterodimers, members of the eukaryotic cytoskeleton. They possess an intrinsic dynamics which is necessary to any cellular functions such as the mitosis. It has long been recognized that GTP hydrolysis in αβ-tubulin polymers plays a critical role in this dynamics as well as the interactions between tubulin and the protein partners or the drugs. In this thesis, molecular modeling approaches are applied to three theoretical studies to gain insight at the atomic scale about tubulin-ligand interactions and to contribute to the development of new active compounds. Molecular dynamics simulations were used to study the effect of the different nucleotide states at β-tubulin on the protofilament structure and dynamics. We propose a role for residue αE254 in catalytic magnesium coordination. We also observe conformational changes and structure rearrangement at lateral and longitudinal interfaces that can affect the microtubule stabilization. Previous work carried out in the laboratory showed that colchicine and carbendazime bind neighboring pockets in the β-tubulin subunit and inhibit cell proliferation. We proposed a binding site of carbendazime on the tubulin-colchicine complex, using docking and molecular dynamics simulation, which lead to the design of hybrid molecules composed of both colchicines and carbendazime moieties attached with a linker. One of these hybrid molecules has been synthesized and successfully tested on HeLa cells. Finally, we designed four cyclic peptides based on I19L, an anti-microtubule peptide identified at the laboratory. Molecular dynamic simulations and binding free energy calculations were used to evaluate these peptides. Mutations were then proposed on the best peptide to increase its interactions with tubulin
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Read, Stuart Hamilton. "Production and function of a soluble c-Kit molecule." Title page, abstract and contents only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phr2845.pdf.
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"Research conducted at the Department of Haematology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science."--T.p. Includes bibliographical references (leaves 170-214). Elevated levels of receptor tyrosine kinases have been implicated in carcinogenesis. It is possible that high expression of c-Kit by the leukaemic cell provides them with a growth advantage over their normal counterparts in the bone marrow microenvironment. Thus, a means of inhibiting the interaction of c-Kit on these cells with ligand Steel Factor may remove proliferation and survival signals. Main aim of the study was to produce a biological inhibitor of this interaction and evaluate its ability to prevent ligand Steel Factor from binding to c-Kit on live cells.
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Croft, Edward. "Computational analyses of protein-ligand interactions." Thesis, University of York, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265562.
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Schwimmer, Lauren J. "Engineering ligand-receptor pairs for small molecule control of transcription." Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-06282005-172608/.
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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006.<br>Doyle, Donald, Committee Chair ; Radhakrishna, Harish, Committee Member ; Bommarius, Andreas, Committee Member ; Orville, Allen, Committee Member ; Seley, Katherine, Committee Member.
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Duer, Melinda J. "The parametric probes of ligand field theory." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304165.
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