Дисертації з теми "Computational docking"
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Totrov, Maxim. "Computational studies on protein-ligand docking." Thesis, Open University, 1999. http://oro.open.ac.uk/58005/.
Повний текст джерелаLivoti, Elsa Livoti. "Experimentally validated computational docking to characterize protein-protein interactions." Thesis, University of Kent, 2017. https://kar.kent.ac.uk/67450/.
Повний текст джерелаMoont, Gidon. "Computational modelling of protein/protein and protein/DNA docking." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445703/.
Повний текст джерелаTantar, Alexandru-Adrian. "Hybrid parallel metaheuristics for molecular docking on computational grids." Thesis, Lille 1, 2009. http://www.theses.fr/2009LIL10166.
Повний текст джерелаThe thesis proposes an extensive analysis of adaptive hierarchical parallel metaheuristics for ab initio conformational sampling. Standing as an NP, combinatorial, highly multi-modal optimization problem, conformational sampling requires for high-performance large scale hybrid approaches to be constructed. Following an incremental definition, minimum complexity conformational sampling mathematical models are first analyzed, entailing a review of different force field formulations. A comprehensive analysis is conducted on a large set of operators and local search algorithms including adaptive and dynamic mechanisms. As determined by the analysis outcomes, complex a priori and online parameter tuning stages are designed. finally, highly scalable hierarchical hybrid distributed algorithm designs are proposed. Experimentation is carried over multiple parallelization models with afferent cooperation topologies. Expenmentations resulted in unprecedented results to be obtained. Multiple perfect conformational matches have been determined, on highly difficult protein structure prediction and molecular docking benchmarks, with RMSD average values below 1.0A. The validation of the proposed hybrid approaehes was performed on Grid'5000, a French computational grid, with almost 5000 computational cores. A Globus Toolkit hased Grid'SOOO system image has been developed, sustaining large scale distributed deployments. The constructed hierarchical hybrid distributed algorithm has been deployed on multiple clusters, with almost 1000 computing cores. Finally, a parallel AutoDock version was developed using the ParadisEO framework, integrating the developed algorithms
Turzo, SM Bargeen Alam. "Computational Investigation of Protein Assemblies." Cleveland State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=csu1532714714406789.
Повний текст джерелаJiménez, García Brian. "Development and optimization of high-performance computational tools for protein-protein docking." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/398790.
Повний текст джерелаGràcies als recents avenços en computació, el nostre coneixement de la química que suporta la vida ha incrementat enormement i ens ha conduït a comprendre que la química de la vida és més sofisticada del que mai haguéssim pensat. Les proteïnes juguen un paper fonamental en aquesta química i són descrites habitualment com a les fàbriques de les cèl·lules. A més a més, les proteïnes estan involucrades en gairebé tots els processos fonamentals en els éssers vius. Malauradament, el nostre coneixement de la funció de moltes proteïnes és encara escaig degut a les limitacions actuals de molts mètodes experimentals, que encara no són capaços de proporcionar-nos estructures de cristall per a molts complexes proteïna-proteïna. El desenvolupament de tècniques i eines informàtiques d’acoblament proteïna-proteïna pot ésser crucial per a ajudar-nos a reduir aquest forat. En aquesta tesis, hem presentat un nou mètode computacional de predicció d’acoblament proteïna-proteïna, LightDock, que és capaç de fer servir diverses funcions energètiques definides per l’usuari i incloure un model de flexibilitat de la cadena principal mitjançant la anàlisis de modes normals. Segon, diverses eines d’interès per a la comunitat científica i basades en tecnologia web han sigut desenvolupades: un servidor web de predicció d’acoblament proteïna-proteïna, una eina online per a caracteritzar les interfícies d’acoblament proteïna-proteïna i una eina web per a incloure dades experimentals de tipus SAXS. A més a més, les optimitzacions fetes al protocol pyDock i la conseqüent millora en rendiment han propiciat que el nostre grup de recerca obtingués la cinquena posició entre més de 60 grups en les dues darreres avaluacions de l’experiment internacional CAPRI. Finalment, hem dissenyat i compilat els banc de proves d’acoblament proteïna-proteïna (versió 5) i proteïna-ARN (versió 1), molt importants per a la comunitat ja que permeten provar i desenvolupar nous mètodes i analitzar-ne el rendiment en aquest marc de referència comú.
Buonfiglio, Rosa <1985>. "Computational strategies to include protein flexibility in Ligand Docking and Virtual Screening." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6330/1/Tesi_Buonfiglio.pdf.
Повний текст джерелаBuonfiglio, Rosa <1985>. "Computational strategies to include protein flexibility in Ligand Docking and Virtual Screening." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6330/.
Повний текст джерелаMoreno, Nascimento Érica Cristina. "Understanding Acetylcholinesterase Inhibitors: Computational Modeling Approaches." Doctoral thesis, Universitat Jaume I, 2017. http://hdl.handle.net/10803/406125.
Повний текст джерелаPatel, Dharmeshkumar. "Computational Studies of Ion Channel Blockers and Protein Aggregation." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17134.
Повний текст джерелаGenheden, Samuel. "A fast protein-ligand docking method." Thesis, University of Skövde, School of Humanities and Informatics, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-69.
Повний текст джерелаIn this dissertation a novel approach to protein-ligand docking is presented. First an existing method to predict putative active sites is employed. These predictions are then used to cut down the search space of an algorithm that uses the fast Fourier transform to calculate the geometrical and electrostatic complementarity between a protein and a small organic ligand. A simplified hydrophobicity score is also calculated for each active site. The docking method could be applied either to dock ligands in a known active site or to rank several putative active sites according to their biological feasibility. The method was evaluated on a set of 310 protein-ligand complexes. The results show that with respect to docking the method with its initial parameter settings is too coarse grained. The results also show that with respect to ranking of putative active sites the method works quite well.
Rodrigues, Caio Henrique Pinke. "Estudos in silico do comportamento de catinonas sintéticas com interesse forense." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-23102018-112244/.
Повний текст джерелаThe emergence of new psychoactive substances (NPSs) has raised many issues in the context of law enforcement and public drug policies. According to the United Nations Office on Drugs and Crime (UNODC), NPS were created as an alternative to forbidden drugs. These new compounds were designed and formulated to escape the drug control legislation, creating a phenomenon that has become an international problem. In Brazil, these substances are controlled and punishable by Law 11,343 / 2006, also known as the Drug Law. This work presents studies on synthetic cathinones with in silico methodology to investigate mechanisms of detection and tendency of action in the human organism. In the detection-related study, we used the reaction of these drugs with fluorescein isothiocyanate (FITC). For this proposal were made studies regarding to the viability of the calculation methods, FITC conformational analysis, energetic evaluation of the reaction with the cathinones and the emission spectra. In relation to the viability of the calculation methods we have that the previous optimization of the compounds involved with the semi-empirical PM6 and subsequent refinement with the B3LYP / 6-31G ** method were adequate for the calculations. The energetic evaluation showed that the reaction is favorable for amphetamines, amino acids and cathinones, and the lowest values were found in the last case. In the emission studies we obtained similar results to the energy profile; however, we observed that the spectra are unique representing a low probability of false positive. Docking evaluations have shown that cathinones have more affinity to the dopaminergic receptor than their homologous amphetamines, confirming experimental data reported in the literature. Finally, the studies carried out in this work demonstrated the importance and the capacity of the in silico methods that present with potential grade in the area and that can be widely used in investigations with different purposes in the forensic field.
FILIPPI, GIULIA. "Computational approaches for the study of biotechnologically-relevant macromolecules." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2016. http://hdl.handle.net/10281/102473.
Повний текст джерелаSharma, S. (Satyan). "Computational Studies on Prostatic Acid Phosphatase." Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289743.
Повний текст джерелаVERTEMARA, JACOPO. "Computational modelling of macromolecules: prediction of the 3-D structure, catalytic activity and dynamic features of proteins." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/198948.
Повний текст джерелаIn this work I used different computational techniques, in particular QM and MM methods, to study the relation between structure and activity. The first project was the characterization under structural point of view of the FeMo-cofactor presents in the active site of nitrogenase. My work was focused on the structural characterization of the key cofactor state E4 , that is now accepted as the intermediate that bind N2 in the active site. For this purpose, DFT simulations have been performed on the FeMo-co active site considering all the iron oxidation state assignments proposed in literature ([ 5Fe III :2Fe II ]; [ 3Fe III :4Fe II ]; [ 1Fe III :6Fe II ]) with protonated and not protonated forms of homocitrate. Only in cases of [ 3F e III :4F e II ] with protonated form of homocitrate the optimized E 4 structure shows two hydrides bridged to the same iron atoms (Fe6 and Fe7 ) in an orthogonal fashion, consistently with experimental data. I have also studied the electronic properties of E 4 intermediate in order to evaluate the spin alignment of ferrous and ferric sites, with peculiar focus on the two Fe ions sharing hydride ligands. DFT broken symmetry calculations showed a parallel spin-coupling pattern for the two iron atoms (↑Fe6 : ↑Fe7 ). Another issue investigated is the effect of the substitution of Ar g 96 → Gln on the resting state of the MoFe protein. Experimental evidences show that in presence of this mutation the active site of nitrogenase is able to (non-covalently) bind acetylene even in the resting state (whereas WT protein cannot). To rationalize the observed behaviour, DFT approach has been used to evaluate the binding energy between acetylene and FeMo-co active site in the cases of mutant and wild type systems. In line with experiments, the binding energy results more favourable for the mutant than for the wild type enzyme. An explanation can be found in the different chemico-physical properties of the region available for acetylene binding in cofactor proximity: in presence of the substitution Ar g 96 → Gln the pocket environment becomes more hydrophobic than in the wild type case. Considering the nonpolar nature of acetylene, the mutated MoFe protein has therefore active site features that make it more suitable for substrate binding. The second project was the characterization of the hydrolytic mechanism of a de novo design peptide TRIL9CL23H (an analogue of carbonic anhydrase) trough DFT calculations and identification of a possible binding site for substrates using flexible docking. The mechanism proposed for TRIL9CL23H is a merge of α-anhydrase and β-anhydrase ones: as in α-anhydrase there is a zinc coordinated by three histidine residues and a water molecule, as in β-anhydrase a glutamate residue accepts the water’s proton from active site. Contrary to carbonic anhydrase, results show that the rate determining step is the release of the products from active site and not the activation of water. According to docking results the binding site is located on the side of proteins close to the active site. The last project has investigated the effect of the R10T amino acid change in the Mre11 protein which causes a rapid DSB resection. The wild type and the mutated dimer of Mre11 were studied trough molecular dynamics simulations. Results pointed out that the R10T substitution alters the mobility of the capping domain of Mre11, movement that is implicated in DNA unwinding. This mutation augments the rotation of the capping domain that can lead to a better DNA unwind activity. In this way nucleases that are involved in the DSB resection can have a better access to the DNA.
Thorsteinson, Nels. "Computational ligand discovery for the human and zebrafish sex hormone binding globulin." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/943.
Повний текст джерелаTrezza, Alfonso. "A novel computational way to unlock drug targets deep and transient secretes." Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1072788.
Повний текст джерелаStanton, Suzanne Louise. "Homology Modeling and Molecular Docking of Antagonists to Class B G-Protein Coupled Receptor Pituitary Adenylate Cyclase Type 1 (PAC1R)." ScholarWorks @ UVM, 2016. http://scholarworks.uvm.edu/graddis/624.
Повний текст джерелаRosell, Oliveras Mireia. "Application of computational docking to the characterization and modulation of protein-protein interactions of biomedical interest." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/673607.
Повний текст джерелаEl estudio de los detalles estructurales en 3D de las interacciones de proteínas es esencial para comprender las funciones biomoleculares a nivel molecular. En este contexto, la disponibilidad limitada de estructuras experimentales de complejos proteína-proteína en resolución atómica está impulsando el desarrollo de métodos de acoplamiento computacional que apuntan a complementar la cobertura estructural actual de interacciones de proteínas. Uno de estos enfoques de acoplamiento es pyDock, que utiliza van der Waals, electrostática y energía de desolvatación para puntuar las poses de acoplamiento generadas por una variedad de métodos de muestreo, generalmente FTDock o ZDOCK. El método ha demostrado un rendimiento de predicción consistentemente bueno en experimentos de evaluación de toda la comunidad como CAPRI o CASP, y ha proporcionado conocimientos biológicos e interpretación profunda de experimentos al modelar muchas interacciones biomoleculares de interés biomédico y biotecnológico. Aquí, describimos nuestro enfoque utilizando pyDock para el modelado estructural de ensamblajes de proteínas y la aplicación de sus módulos a diferentes fenómenos de reconocimiento biomolecular, como el modelado del modo de unión, la interfície y la predicción de puntos calientes, el uso de restricciones basadas en datos experimentales, la inclusión de datos estructurales de baja resolución, estimación de afinidad de unión o modelado de ensamblajes homo- y hetero- oligoméricos. La integración de enfoques de acoplamiento ab initio y basados en plantillas está emergiendo como la estrategia óptima para modelar complejos de proteínas y ensamblajes multimoleculares. Revisaremos los nuevos avances metodológicos sobre el acoplamiento ab initio y el modelado integrativo. La séptima edición de CAPRI impuso nuevos desafíos al modelado de complejos proteína-proteína, como la oligomerización multimérica, las interacciones proteína-péptido y proteína-oligosacárido. Muchos de los objetivos propuestos necesitaban la integración eficiente de acoplamiento de cuerpo rígido, modelado basado en plantillas, optimización flexible, puntuación multiparamétrica y restricciones experimentales. Esto fue especialmente relevante para los conjuntos multimoleculares propuestos en las rondas conjuntas CASP13-CAPRI46. Presentaremos los resultados para la séptima edición de CAPRI y la Ronda 46 de CAPRI, el tercer desafío de predicción del ensamblaje de proteínas CASP-CAPRI conjunto. Uno de los efectos potenciales conocidos de las sustituciones de aminoácidos que causan enfermedades en las proteínas es modular las interacciones proteína-proteína (PPI). Para interpretar tales variantes a nivel molecular y obtener información útil con fines de predicción, es importante determinar si están ubicadas en interfaces proteína-proteína, que se componen de dos regiones principales, núcleo y borde, con diferente conservación evolutiva y diferentes propiedades fisicoquímicas. En la tesis, hemos realizado un análisis estructural, energético y computacional de interacciones entre proteínas que albergan mutaciones relacionadas con enfermedades detectadas en el cribado neonatal. Los residuos de interfície se clasificaron como núcleo o borde, lo que demuestra que los residuos del núcleo son los que más contribuyen a la energía libre de unión del PPI. Es más probable que las variantes que causan enfermedades se produzcan en la región del núcleo de la interfície que en el borde de la interfície de la proteína (p <0,0001). Por el contrario, las variantes neutrales se encuentran más a menudo en el borde de la interfície o en la superficie que no interactúa en lugar de en la región del núcleo de la interfície. También encontramos que la arginina, el triptófano y la tirosina están sobrerrepresentados entre los residuos mutados que conducen a la enfermedad. Estos resultados pueden mejorar nuestra comprensión de las enfermedades a nivel molecular y, por lo tanto, contribuir a la medicina personalizada al ayudar a los médicos a proporcionar diagnósticos y tratamientos adecuados. Los efectos fenotípicos de variaciones genéticas no-sinónimas que conducen o predisponen a la enfermedad pueden racionalizarse sobre la base del impacto funcional y estructural en la proteína mutada, incluida la perturbación de la red de interacción y las vías moleculares en las que participa dicha proteína. Por lo tanto, comprender estos efectos a nivel molecular es esencial para construir modelos de enfermedad precisos y lograr una mayor precisión en el diagnóstico y la intervención terapéutica. En este contexto, podemos caracterizar computacionalmente el efecto de mutaciones patológicas en interacciones proteína-proteína específicas ("edgetic"), en base a su estructura proteica, si está disponible, o en modelos de acoplamiento. Las interacciones proteína-proteína que están claramente estabilizadas o desestabilizadas por estas mutaciones pueden ser objetivos potenciales para la intervención terapéutica. Hemos analizado el efecto energético predicho de las mutaciones en los PPI aplicando una variedad de métodos informáticos para modelar la mutación y calcular el cambio en la afinidad de unión (FoldX, mCSM, pyDock combinados con SCWRL3). Validamos el impacto energético predictivo a través de mutaciones experimentales contenidas en SKEMPI 2.0 y aplicamos estos enfoques en variantes patológicas y neutrales de un solo aminoácido (SAV en inglés) posteriormente (de ClinVar / Humsavar y gnomAD). En base a esto, hemos identificado mutaciones patológicas que inciden claramente en las interacciones analizadas estabilizándolas o desestabilizándolas. Como se ha discutido, las interacciones proteína-proteína son importantes para procesos biológicos y situaciones patológicas y son objetivos atractivos para el descubrimiento de fármacos. Sin embargo, el diseño racional de fármacos dirigidos a las interacciones proteína-proteína sigue siendo un gran desafío. Los residuos de puntos calientes se consideran la mejor opción para apuntar a tales interacciones, pero su identificación requiere una caracterización estructural y energética detallada, que solo está disponible para una pequeña fracción de interacciones de proteínas. Esta tesis doctoral cubre una variedad de métodos computacionales que han sido reportados para el análisis energético de interfícies proteína-proteína en la búsqueda de puntos calientes y el modelado estructural de complejos proteína-proteína por acoplamiento. Esto puede ayudar a racionalizar el descubrimiento de inhibidores de moléculas pequeñas de interfícies proteína-proteína de interés terapéutico. El análisis computacional y el acoplamiento pueden ayudar a localizar la interfície, la dinámica molecular se puede utilizar para encontrar cavidades adecuadas y las predicciones de puntos calientes pueden enfocar la búsqueda de inhibidores de interacciones proteína-proteína. Una dificultad importante para aplicar métodos racionales de diseño de fármacos a las interacciones proteína-proteína es que en la mayoría de los casos no se dispone de la estructura compleja. Afortunadamente, el acoplamiento computacional puede complementar los datos experimentales. Un aspecto interesante para explorar en el futuro es la integración de estas estrategias para apuntar a las interacciones proteína-proteína con análisis mutacionales a gran escala.
Paissoni, C. "COMPUTATIONAL TECHNIQUES TO EVALUATE AT ATOMIC LEVEL THE MECHANISM OF MOLECULAR BINDING." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/480031.
Повний текст джерелаLemke, Oliver [Verfasser]. "Theoretical Analysis of Biomolecular Systems: Computational Simulations, Core-set Markov State Models, Clustering, Molecular Docking / Oliver Lemke." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1205735461/34.
Повний текст джерелаChen, Sih-Yu. "Computational studies of biomolecules." Thesis, University of St Andrews, 2017. http://hdl.handle.net/10023/11064.
Повний текст джерелаASTHANA, SHAILENDRA. "A computational approach for identification and development of novel inhibitors targeting viral polymerases." Doctoral thesis, Università degli Studi di Cagliari, 2011. http://hdl.handle.net/11584/266286.
Повний текст джерелаBasili, Serena. "Computational Approaches for the Rational Design of Novel Topoisomerase I Poisons as Potential Anticancer Drugs." Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3426128.
Повний текст джерелаLa Topoisomerasi I eucariotica (TopoI) è un enzima essenziale che modifica il grado di superavvolgimento del DNA mediante un processo di rottura e successiva ricongiunzione di uno dei due filamenti del DNA, regolandone lo stato topologico richiesto nei processi di replicazione e di trascrizione. Il rilassamento del DNA superavvolto indotto dalla TopoI avviene attraverso la rottura transitoria di un filamento per mezzo di una reazione di transesterificazione. Quest'ultima coinvolge l'attacco nucleo lo da parte del gruppo ossidrilico di un residuo di tirosina (Tyr723) del sito attivo dell'enzima ad un legame fosfodiesterico del DNA a livello del sito di taglio, con formazione di un complesso covalente 3'-fosfotirosina TopoI-DNA (noto anche come cleavable complex). La rotazione del filamento tagliato intorno a quello intatto rende possibile il rilassamento della molecola di DNA. Il complesso binario covalente subisce in seguito un attacco nucleofilo a livello della fosfotirosina da parte dell'estremità libera 5'-OH del lamento rotto, che permette la riformazione del legame fosfodiesterico. La TopoI è il target specifico dell'alcaloide pentaciclico Camptotecina (CPT), isolato per la prima volta nel 1966 dalla corteccia di Camptotheca Acuminata, e dei suoi derivati, noti come veleni di TopoI. Queste molecole bloccano il processo di ricongiunzione del filamento di DNA tagliato, convertendo la TopoI in un agente dannoso per il DNA stesso. Queste molecole si intercalano tra le basi del DNA a livello del sito di taglio dando luogo alla formazione di un complesso ternario con la TopoI e il DNA. La maggiore stabilità del complesso ternario rispetto al complesso binario TopoI-DNA risulta in un aumento del tempo di vita del DNA tagliato. Poiché la presenza del veleno induce il disallineamento dell'estremità libera 5'-OH del filamento rotto con il legame fosfotirosinico, il processo di ricongiunzione non può avvenire. Questo porta all'attivazione di una serie complessa di segnali intracellulari, il cui risultato ultimo è la morte della cellula per apoptosi. Di conseguenza, le molecole in grado di formare complessi ternari stabili hanno attività antitumorale. L'utilizzo clinico della CPT è ostacolato sia dalla sua scarsissima idrosolubilità, sia perchè la sua forma attiva lattonica “chiusa” è rapidamente convertita, in condizioni fisiologiche, nella forma carbossilica “aperta”, che è inattiva e si lega in elevata percentuale all'albumina serica. Attualmente solo due derivati semisintetici della CPT (Topotecan ed Irinotecan) sono utilizzati nella pratica clinica per il trattamento di cancro ovarico, polmonare e colo-rettale. La recente risoluzione, mediante cristallografia a raggi X, della struttura tridimensionale di TopoI in complesso sia con la Camptotecina e il Topotecan che con derivati strutturalmente diversi (indolocarbazolici ed isochinolinici), ha fornito chiarimenti sulle caratteristiche dell'interazione enzima-inibitore. Tali informazioni costituiscono elementi molto utili nello studio dei veleni di TopoI con un approccio di tipo computazionale il cui scopo è comprendere in che modo queste molecole interagiscono con il loro target e progettare nuovi nuovi derivati come potenziali farmaci ad attività antitumorale. È stato quindi possibile individuare un nuovo farmacoforo sfruttando le cinque strutture cristallogra che disponibili, al fine di rintracciare un set di caratteristiche strutturali comuni a tutti i veleni di TopoI. Con lo scopo di disporre di nuovi derivati più semplici da ottenere dal punto di vista della sintesi ma che mantengano tutte le caratteristiche farmacoforiche richieste per la formazione di complessi ternari stabili con TopoI e DNA, è stata proposta la sintesi di analoghi “semplificati” della CPT. Si può infatti ipotizzare che una molecola non debba necessariamente possedere uno scaffold pentaciclico per legarsi al complesso binario TopoI-DNA, purchè mantenga un sistema planare aromatico per intercalare il DNA e opportuni gruppi funzionali in grado di interagire con specifici aminoacidi dell'enzima. Sulla base di questa assunzione, diversi possibili scaffold sono stati disegnati e sottoposti a studi di docking con diversi protocolli di ricerca per predire la loro capacità di formare stabili complessi ternari con TopoI e DNA. È stato inoltre condotto uno studio di docking molecolare per una serie di nuovi derivati della CPT sostituiti in posizione 5 (5-derivati) per descrivere la loro modalità di interazione con il complesso TopoI-DNA. In generale, l'introduzione di sostituenti in posizione 5 ha come risultato una diminuzione dell'attività citotossica rispetto alla CPT. La presenza di sostituenti lipofili di piccole dimensioni sembra essere tollerata all'interno del sito di binding, mentre l'introduzione di gruppi idro lici dà luogo ad una diminuzione dell'affinità. L'introduzione di gruppi stericamente ingombranti provoca la perdita di importanti interazioni al'interno del sito di legame. I risultati computazionali indicano come caratteristica generale che l'epimero ? dei 5-derivati ha un'affinità maggiore per il sito di binding rispetto all'epimero ?. Recentemente sono stati sintetizzati una serie di 16a-tio-CPT analoghi. I saggi biologici condotti su questi composti hanno rivelato che i tio-derivati sono potenti inibitori della TopoI ed hanno attività antitumorale maggiore rispetto ai loro oxo-analoghi, sia in vitro che in vivo. Al fine di razionalizzare la maggiore attività dei tio-analoghi rispetto ai derivati tradizionali, è stato eseguito uno studio computazionale volto sia a predire proprietá chimico-fisiche rilevanti per la descrizione del possibile profilo farmacocinetico delle nuove molecole, sia a descriverne la modalità di legame nel sito del complesso binario TopoI-DNA tramite studi di docking. I risultati di docking non hanno messo in evidenza differenze di rilievo tra i tio- e gli oxo-derivati in termini di modalità di binding e di docking score. Al contrario, i valori predetti per proprietà come la lipofilicità, la solubilità in acqua e la permeabilità cellulare indicano che il profilo farmacocinetico delle due classi di composti potrebbe essere significativamente diverso. Per le simulazioni di docking condotte sui 5-CPT-derivati e sui tio-CPT-derivati è stato utilizzato il protocollo quantum mechanics (QM)-polarized ligand docking (QPLD) (implementato nella suite Schrödinger) con lo scopo di aumentare l'accuratezza dei calcoli di docking. I metodi tradizionali utilizzati per il docking molecolare utilizzano una rappresentazione chimico-fisica approssimata delle interazioni proteina-ligando, dove le cariche atomiche sono calcolate in base al campo di forza. Il protocollo QPLD utilizza invece una metodologia ab initio per il calcolo delle cariche del ligando all'interno della cavità della proteina, tenendo in considerazione la polarizzazione di carica indotta dagli aminoacidi del sito di legame sul ligando. Il lavoro relativo ai 5-CPT-derivati e ai tio-CPT-derivati à stato supportato dall'azienda farmaceutica Indena S.p.A., Milano, Italia. Il lavoro è stato condotto in collaborazione con il gruppo del Professor Arturo Battaglia (Centro Nazionale Richerche Bologna) per la sintesi dei composti e con il gruppo del Professor Franco Zunino (Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano) per i saggi biologici.
Robertson, Cole D. "A Computational and Design Characterization for the Flowfield behind a C-130 during an Unmanned Aerial Vehicle Docking." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1563533448658585.
Повний текст джерелаCANTARINI, MATTIA. "Melatonin agonists for glaucoma treatment: a computational strategy for the search of active compounds and their delivery in the eye." Doctoral thesis, Università Politecnica delle Marche, 2022. http://hdl.handle.net/11566/299601.
Повний текст джерелаGlaucoma is a group of ocular neuropathies characterized by a progressive and irreversible loss of vision. Currently, pharmacological therapies aim to decrease intraocular pressure (IOP), a modifiable risk factor to lower glaucoma progression. As the natural ligand melatonin has a short half-life and low bioavailability, in this research, in silico techniques were used to detect bioactive compounds with high affinity for melatonin receptors (MTs) and low toxicity that could be immediately used for the treatment of glaucoma. To reach that aim, starting from known agonistic compounds, it was investigated the molecular basis of the ligand recognition and agonistic activity for hMTs. The melatonin bioisostere agomelatine have been chosen because of its high stability and melatonergic activity. In addition, this compound has high affinity and antagonistic activity for the human serotonin receptor 5HT2C, whose inhibition seems to be involved in the IOP control. Starting from these results, we went further to in silico screening huge libraries of compounds (both natural, psychoactive and nootropic drugs) towards the macromolecular targets hMTs and h5HT2C, selecting the most promising ones that were then tested in vivo on animal model of rat. Pharmacophoric search was realized to build new molecular libraries based on the features of well-known melatonergic agonists. Finally, in order to study a liposomal formulation able to increase the melatonin stability in solution, further in silico studies were carried out in order to evaluate the extent of melatonin absorption inside lipid bilayer in different saline solutions and concentrations just used in ophthalmologic field.
Collar, Catharine Jane. "Rational Drug Design for Neglected Diseases: Implementation of Computational Methods to Construct Predictive Devices and Examine Mechanisms." Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/chemistry_diss/48.
Повний текст джерелаMucs, Daniel. "Computational methods for prediction of protein-ligand interactions." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/computational-methods-for-prediction-of-proteinligand-interactions(33ad0b24-ef7b-4dff-8e28-597a2f34e079).html.
Повний текст джерелаGhiasi, 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.
Повний текст джерелаLindh, Martin. "Computational Modelling in Drug Discovery : Application of Structure-Based Drug Design, Conformal Prediction and Evaluation of Virtual Screening." Doctoral thesis, Uppsala universitet, Avdelningen för organisk farmaceutisk kemi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-328505.
Повний текст джерелаScott, Sharon Elizabeth. "Computational Approaches to Studying Organic Cation Sorption to Organic Matter." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1594139918499603.
Повний текст джерелаJaiyong, Panichakorn. "Computational modelling of ligand shape and interactions for medicines design." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/computational-modelling-of-ligand-shape-and-interactions-for-medicines-design(28d49921-447f-4ea1-aaf2-aa764f45b2f2).html.
Повний текст джерелаYasmin, Sabina. "Computational Studies of Plant Toxin Blockers of Potassium Channels, and Affinity & Aggregation of Antibodies." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18907.
Повний текст джерелаEklund, Robert. "Computational Analysis of Carbohydrates : Dynamical Properties and Interactions." Doctoral thesis, Stockholm : Department of Organic Chemistry, Stockholm University, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-538.
Повний текст джерелаSantiago, Daniel Navarrete. "Use and Development of Computational Tools in Drug Discovery: From Small Molecules to Cyclic Peptides." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4398.
Повний текст джерелаPatschull, Lafitte-Laplace Anathe Olivia Maria. "In silico ligand fitting/docking, computational analysis and biochemical/biophysical validation for protein-RNA recognition and for rational drug design in diseases." Thesis, Birkbeck (University of London), 2014. http://bbktheses.da.ulcc.ac.uk/84/.
Повний текст джерелаRoss, Gregory A. "Improving rapid affinity calculations for drug-protein interactions." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:62ccfb5e-10f1-40ec-9a2b-936277944d87.
Повний текст джерелаARTESE, ANNA. "Computational studies of mutations associated to resistance in HIV-1 macromolecular targets and implications in rational design of novel antiviral agents." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2008. http://hdl.handle.net/2108/424.
Повний текст джерелаIn order to discover novel selective anti-HIV resistance-evading drugs, a theoretical study was carried out combining structural analysis of RT crystallographic models, clinical data about RT conserved residues and an innovative computational method based on GRID maps. Such analysis allowed to reproduce clinical results and to highlight the consequences of the mutations in the recognition step. Moreover the computational approach generated a pharmacophore model useful for the design of novel RT inhibitors. The presence of the I135T polymorphism in NNRTI-naive patients significantly correlated with the appearance of K103N in cases of NNRTI failure, suggesting that I135T may represent a crucial determinant of NNRTI resistance evolution. Molecular Dynamics simulations (MD) showed that I135T can contribute to the stabilization of the K103N-induced closure of the NNRTI binding pocket by reducing the distance and increasing the number of hydrogen bonds between 103N and 188Y. In addition the influence of two drug resistance-associated mutations, L33F and L76V, of HIV-1 PR has been evaluated with respect to lopinavir (LPV) and atazanavir (ATV) molecular recognition. The evaluation of the interaction energies after the MD revealed that L33F substitution is related to reduced host/guest interactions, decreased affinity and to a dimer destabilizing effect for both PR inhibitors. In presence of L76V mutation, LPV showed a lowered binding affinity and a reduced hydrogen bonding network, while ATV complexes revealed a more productive binding affinity, increased host/guest interactions and dimer stabilizing effects, in agreement with hyper susceptibility data. With the aim to estimate the stability of its 6-helix bundle, the gp41 conformational properties were investigated in presence of V38A and N140I, known enfuvirtide resistance-associated mutations. MD showed that the co-presence of V38A+N140I abolished the interaction between residue 38 and 145 important for the 6-helix-bundle stabilization.
Abdulganiyyu, Ibrahim A. "A single AKH neuropeptide activating three different fly AKH-receptors: an insecticide study via computational methods." Doctoral thesis, Faculty of Science, 2021. http://hdl.handle.net/11427/33621.
Повний текст джерелаParra, Katherine Cristina. "Combination of the Computational Methods: Molecular dynamics, Homology Modeling and Docking to Design Novel Inhibitors and study Structural Changes in Target Proteins for Current Diseases." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5093.
Повний текст джерелаMarín, López Manuel Alejandro 1987. "On the development of computational tools for the study of protein-protein interactions and protein-protein binding." Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/565599.
Повний текст джерелаLes proteïnes estan implicades en gairebé tots els processos cel·lulars, amb la interacció física entre elles clau per la seva funció i dictada per la seva estructura 3D. Per tant, l’estudi de la unió i les interaccions proteïna-proteïna és crucial per entendre completament els sistemes biològics. En aquesta tesi, es presenta V-D2OCK, una eina de “docking” dirigit ràpida i precisa per predir l’estructura de complexes de proteïnes a gran escala. També hem estudiat l’espai conformacional de possibles complexes transitoris per mitjà de resultats de “docking” no específics per tal de desenvolupar BADock, un predictor d’energia d’unió a partir de les estructures individuals per separat. Finalment, hem publicat online un recurs integrat i centralitzat (InteractoMIX) que permet a la comunitat investigadora l’accés fàcil a un conjunt de aplicacions web de bioinformàtica per l’estudi de interaccions proteïna-proteïna.
Berry, Michael. "Massively-Parallel Computational Identification of Novel Broad Spectrum Antivirals to Combat Coronavirus Infection." University of the Western Cape, 2015. http://hdl.handle.net/11394/8321.
Повний текст джерелаGiven the significant disease burden caused by human coronaviruses, the discovery of an effective antiviral strategy is paramount, however there is still no effective therapy to combat infection. This thesis details the in silica exploration of ligand libraries to identify candidate lead compounds that, based on multiple criteria, have a high probability of inhibiting the 3 chymotrypsin-like protease (3CUro) of human coronaviruses. Atomistic models of the 3CUro were obtained from the Protein Data Bank or theoretical models were successfully generated by homology modelling. These structures served the basis of both structure- and ligand-based drug design studies. Consensus molecular docking and pharmacophore modelling protocols were adapted to explore the ZINC Drugs-Now dataset in a high throughput virtual screening strategy to identify ligands which computationally bound to the active site of the 3CUro . Molecular dynamics was further utilized to confirm the binding mode and interactions observed in the static structure- and ligand-based techniques were correct via analysis of various parameters in a IOns simulation. Molecular docking and pharmacophore models identified a total of 19 ligands which displayed the potential to computationally bind to all 3CUro included in the study. Strategies employed to identify these lead compounds also indicated that a known inhibitor of the SARS-Co V 3CUro also has potential as a broad spectrum lead compound. Further analysis by molecular dynamic simulations largely confirmed the binding mode and ligand orientations identified by the former techniques. The comprehensive approach used in this study improves the probability of identifying experimental actives and represents a cost effective pipeline for the often expensive and time consuming process of lead discovery. These identified lead compounds represent an ideal starting point for assays to confirm in vitro activity, where experimentally confirmed actives will be proceeded to subsequent studies on lead optimization.
Brown, Jason David. "A Computational Investigation Into the Development of an Effective Therapeutic Against Organophosphorus Nerve Agent Exposure." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1416836502.
Повний текст джерелаPavlovicz, Ryan Elliott. "Investigation of Protein/Ligand Interactions Relating Structural Dynamics to Function: Combined Computational and Experimental Approaches." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397220613.
Повний текст джерелаVyas, Shubham. "Computational And Experimental Studies Towards The Development Of Novel Therapeutics Against Organophosphorus Nerve Agents: Butyrylcholinesterase And Paraoxonase." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1309974326.
Повний текст джерелаSkone, Gwyn S. "Stratagems for effective function evaluation in computational chemistry." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:8843465b-3e5f-45d9-a973-3b27949407ef.
Повний текст джерелаShamsudin, Khan Yasmin. "Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2 : Binding modes and mechanisms from computational methods and free energy calculations." Doctoral thesis, Uppsala universitet, Beräkningsbiologi och bioinformatik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-328478.
Повний текст джерелаUsié, Chimenos Anabel. "Development of computational tools to assist in the reconstruction of molecular networks." Doctoral thesis, Universitat de Lleida, 2014. http://hdl.handle.net/10803/129848.
Повний текст джерелаEl objetivo de esta tesis es desarrollar e implementar un conjunto de herramientas de minería de datos para ayudar en la reconstrucción de circuitos biológicos a través del análisis y la integración de grandes conjuntos de datos biológicos. Estos circuitos son importantes porque regulan todos los procesos que controlan la vida y la salud de los organismos. El trabajo principal de la tesis se centra en el análisis de los datos bibliómicos, desarrollándose con este fin dos herramientas diferentes, Biblio-MetReS para la reconstrucción de redes PPIs y la identificación de los procesos en que intervienen estas redes, y CheNER para la identificación de nombres de compuestos químicos. La herramienta final que he desarrollado se centra en la integración de métodos para el análisis estructural y modelado de proteínas con métodos de acoplamiento para la predicción de complejos físicos de proteína-proteína.
The aim of this thesis is the development and implementation of a set of data mining tools to aid in the reconstruction of biological circuits through analysis and integration of large biological datasets. These circuits are important because they regulate and maintain life and health in organisms. The main part of the thesis is focused on analyzing bibliomic data for which I develop two tools, Biblio-MetReS for the reconstruction of PPIs networks and to identify the processes in which the networks are involved, and CheNER for the identification of chemical compounds names. The final tool developed focuses on the integration of methods for structural analysis and modeling of proteins with docking methods for prediction of native protein-protein physical complexes.
Alonso, Hernan, and hernan alonso@anu edu au. "Computer Modelling and Simulations of Enzymes and their Mechanisms." The Australian National University. The John Curtin School of Medical Research, 2006. http://thesis.anu.edu.au./public/adt-ANU20061212.161155.
Повний текст джерелаGULOTTA, Maria Rita. "Computational methodologies applied to Protein-Protein Interactions for molecular insights in Medicinal Chemistry." Doctoral thesis, Università degli Studi di Palermo, 2021. http://hdl.handle.net/10447/479127.
Повний текст джерела