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1
Attardo, Giorgio G. (Giorgio Giovanni). "Drug design and synthesis of novel heteroanthracycline antitumor drugs." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74641.
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Novel heteroanthracycline antitumor drugs were designed based on structure activity relationship studies and known mechanisms of drug action. Their preparation required the development of a general synthetic approach.After extensive studies, three methodologies were developed for the general synthetic plan. The first method involved photoenolisation of 2,5-dimethoxybenzaldehyde and SO$ sb2$ entrapment of the o-quinodimethane to give 4,7-dimethoxy-1-hydroxy-1,3-dihydrobenzo(2,3-c) thiophene-2,2-dioxide. This compound served as a general intermediate towards the synthesis of several heteroanthracyclinones. It could be reduced to the oxathiin-2-oxide derivative which thermally extruded SO$ sb2$ to yield the o-quinodimethane. Reentrapment of this latter intermediate with various glyoxalates gave key isochroman derivatives. The second method is an improvement over the first. Isochromandiones with a C-1 hydroxyl functionality were prepared from oxidative demethylation of 1-hydroxyisochromans. These were obtained after acid hydrolysis of the coupling products between epoxides and the cuprate of 2,5-dimethoxy-6-methylbenzaldehydedioxane acetal. The third method involved a sequential cycloaddition routine with two o-quinodimethanes.
By combining newly developed techniques with known methods, a general synthetic plan was developed. Consequently, the total synthesis of six tetracyclic structural hybrids of the naphthoquinone(2,3-c) pyranyl class of antibiotics was accomplished; along with the total synthesis of (R) and (S) 1-(4$ sp prime$-O-p-nitrobenzoyl-N-trifluoroacetyldaunosamine)-$ 1,3$-dihydrothioxantho(2,3-c) thiophene-2,2-dioxide, p-nitrobenzyl(5,12-dihydroxy-3,4-dihydrothioxantho(2,3-c) and (3,2-c) pyran-3-yl)formate, and eight novel heteroanthracyclines with the 5,12-dioxo-2,3,5,12-tetrahydroanthraceno(2,3-c) pyranyl backbone. The diastereomeric mixture of (1$ sp prime$S, 1R, 3S) and (1$ sp prime$S, 1S, 3R) methyl(11-hydroxy-1-$(2 sp prime,3 sp prime,6 sp prime $-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-$5,12 $-dioxo-3,4,5,12-tetrahydroanthraceno(2,3-c) pyran-3-yl) formate was found to possess equipotent antileukemic activity to doxorubicin with no cross resistance.
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Clifton, Heather A. "Computational antiviral drug design." Muncie, Ind. : Ball State University, 2009. http://cardinalscholar.bsu.edu/645.
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Kandil, Sahar. "Computer aided drug design." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/55845/.
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Hepatitis C virus (HCV) chronic infection represents one of the major and still unresolved health problems. HCV infecting 3% of the world population, leading to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in addition to the extrahepatic manifestations. No efficient therapy exists; the standard dual treatment with peg IFN-alpha and ribavirin is effective only in 55% of the selected cases with substantial side effects in addition to the high cost. To date, there is no vaccine against HCV due to the high variability of the RNA genome. NS3 helicase is one of the non-structural proteins whose activity is indispensable for viral RNA replication and its inhibition is estimated to arrest viral proliferation and indirectly stimulate a cellular antiviral response against ds RNA. In our project we proposed to use structure based knowledge of the x-ray crystal structure of helicase enzyme to design and synthesise different scaffolds of novel potential HCV NS3 helicase inhibitors. Using different computer software packages, we manage to design a number of small focused libraries of compounds, which were used for docking simulations. The results obtained in silico guided the selection of two series of promising compounds for synthesis. In the first series; several quinazoline derivatives were prepared and evaluated for antiviral activity in subgenomic replicon assay showing EC50 in the low muM range with relatively high selectivity index. In the second series of pyrrole or phenyl based compounds, irreversible inhibition of helicase is assumed through addition to the electrophilic warheads of the alpha,beta-unsaturated ketones, thiols or 1,2,4 thiadiazoles based inhibitors. Among the synthesised compounds a number showed a sub muM activity in the helicase enzyme assay. These promising findings are considered to be a starting point for further optimisation of structure, activity and toxicity relationships.
4
Zhang, Huarui. "Design, synthesis and activity evaluation of novel exosome inhibitors." HKBU Institutional Repository, 2020. https://repository.hkbu.edu.hk/etd_oa/849.
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Background: Exosomes are extracellular vesicles (EVs) that produced in the endosomal compartment of most eukaryotic cells, and have observed increasing attentions over the past decades. They play important roles in cell- to-cell communications, they can carry varieties of substances, like proteins, nucleic acids and lipids, to the target cells they encounter. These cargos could influence the function of recipient cells. This novel mode of intercellular communication is found to be of critical importance to many cellular activities. However, exosomes are involved in various diseases processes. Tumor- derived exosomes could promote cancer progression, and our preliminary study indicated that exosome released from osteoclasts could inhibit bone formation. We also found that osteoarthritis (OA) progression in OA mice could be attenuated by inhibiting exosomes released by osteoclasts. Therefore, inhibition of exosome release has potential value in the treatment of diseases. The exosome release is under control by RAB27A, which is a protein involved in protein transport and signal transduction. It is reported that a compound named Nexinhib20 could selectively inhibit RAB27A, but this compound is highly toxic to RAW264.7 cells, which IC 50 is 1.5 µM. Therefore, for safety concerns, it has to be chemically modified to reduce toxicity. Aim: (1) To design and synthesize a series compounds based on the structure of Nexinhib20. (2) To evaluate the toxicity and exosome inhibiting activity of the synthesized compounds and discuss the structure-activity relationships (SAR) of them. Materials and Methods: Nexinhib20 derivatives were synthesized by aldol reaction. The cytotoxicity of these compounds was evaluated by MTT assay. The exosome inhibiting activity of these compounds was evaluated through exosome isolation and quantitation. Result: A series of compounds were synthesized and their structures were confirmed by LC-MS and NMR. The structure-activity relationships of these compounds were discussed, and the results showed that compounds A3, A23 and B2 exhibited lower toxicity compared to Nexinhib20 and strong exosome inhibiting ability. Conclusion: The results of this project indicate that A3, A23 and B2 exhibited low toxicity and good exosome inhibiting activity. Based on this, further chemical modification could be applied to develop new exosome inhibitors with better efficacy
5
Ma, Haiqiu. "The formulation, manufacture and evaluation of capsules containing freeze-dried aqueous extracts of Leonotis Leonorus or Mentha Longifolia." Thesis, University of the Western Cape, 2006. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_3777_1181559333.
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Leonotis leonorus and Mentha longifolia are two herbs commonly used in South Africa, mostly in oral liquid dosage forms. Several disadvantages are associated with these traditional dosage forms which can perhaps be remedied by using an appropriate oral solid dosage form, provided the actual plant material in the latter still resemble, as closely as possible, the traditionally used material and provide products of suitable pharmaceutical quality. The objectives of this study were to prepare and evaluate the pharmaceutical suitability of the freeze-dried aqueous extracts of Leonotis Leonorus and Mentha Longifolia as plant raw material for the capsule dosage of these two therapies and to formulate and manufacture capsules of Leonotis Leonorus and Mentha Longifolia aqueous extract that would contain amounts of the plant materials equivalent to that found in their traditional liquid dosage forms, and have immediate release characteristics and suitability stability.
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Remez, Vinogradov Nikita 1985. "Drug design at biological systems level." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/396352.
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The explosion of reductionist approaches at the end of the XXth
century allowed for fast and high-throughput data collection in
pharmaceutical industry, but did not deliver the expected gain in
drug discovery performance. Omics methodologies were able to
provide large amounts of information on one-to-one cause-effect
relationships, but could not explain some of the complex effects in
living organisms and biological systems in general. This Thesis,
performed in the premises of an emerging biotech company,
represents an attempt to explore the impact of an integrative
systems approach to drug discovery. On the one hand, in silico
prediction of drug-target interactions developed at Chemotargets
was applied to the identifcation of cancer-relevant targets, the
design of a biologically diverse chemical library, and the
implementation of a novel methodology for predictive drug safety.
On the other hand, major efforts were devoted to develop and
carefully validate a new approach to anticipating in vivo organ
toxicities from in vitro pharmacological profles and gene expression
datas. This novel methodology was designed to complement and
assist the expert toxicologist by providing insights at the anatomical
level . Last but no least, key contributions have been made to develop
a brand new platform-independent version of the company’s flagship
software, CT-link, allowing for easy distribution and
commercializationA les darreries del segle XX, l'auge de les aproximacions reduccionistes van permetre a la industria farmacèutica la recopilació de gran quantitat de informació, pero l’impacte en el rendiment de la producció de nous fàrmacs no va ser l’esperat. Encara que es van extreure moltes dades sobre les relacions un-a-un entre entitats sistèmiques els efectes complexos causats als sistemes biològics no es van poder adreçar adequadament. Aquesta tesi, desenvolupada en el marc d’una empresa biotecnolòica emergent, intenta introduir un marc de referència integral per l’aproximació sistèmica al disseny de fàrmacs. D'una banda, s’ha aplicat la predicció in silico de xarxes fàrmac-diana per identifcar les proteïnes relacionades amb càncer, per la construcció d’una biblioteca química d’amplia cobertura biològica i per anticipar la toxicitat relacionada amb dianes secundàries. D'altra banda, es va ampliar l’aproximació de biologia de sistemes per abastar les connexions anatòmiques. Aquesta nova metodologia fou dissenyada per complementar i assistir al toxicòleg expert en la identificació de toxicitats a nivell anatòmic. Finalment, durant aquests anys s’ha contribuit de manera important al desenvolupament d’una nova versió independent de la plataforma del programari estrella de l’empresa, CT-link, que n’ha facilitat enormement la seva distribució i comercialització.
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Scott, Richard Kennedy. "Protein modelling and associated drug design." Thesis, University of Newcastle Upon Tyne, 1993. http://hdl.handle.net/10443/523.
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Part one covers an investigation into the secondary and tertiary structure of the protein Xylanase found in Pseudomonasfluorescens subspecies cellulosa. Part two documents the Computer Aided Design of Novel Quinazoline Antifolates for the enzyme Thyrnidylate Synthase. Partone Mature Xylanase protein consists of two distinct regions - a cellulose binding domain and a catalytic region, A and B respectively. Computer modelling of tertiary structure from primary sequence and secondary turn information proved difficult in the absence of experimental X-ray crystal data. Consequently,a series of modified proteins bbased on the Xylanase were prepared by Recombinant DNA technology for extraction and purification. The modified proteins were to be used as a bench mark for quantitative and definitive calculation and detennination of the secondary structure of the xylanase. This was to provide an excellent reference point for theoretical modelling of tertiary structure. Part one of the Thesis documents Computer Modelling work and protein purification and extraction of the xylanase. Part two Thymidylate Synthase (TS) exists as dimer with a single active site in each subunit. It has been crystallised in two forms; a "reduced" (major), and "oxidised" (minor) form. The major form of TS contains dUMP covalently bound to cysteine in both active sites and in the presence of CB3717. One active site of the minor form contains dUMP non-covalently bound and in the presence of CB3717 while the other active site contains only inorganic phosphate and CB3717. The active site of TS is a large cavity that binds CB3717 into two possible confirmations. One is seen in the major form and one in the minor form. Part two of my research documents an investigation into enzyme/inhibitor interaction in TS and covers the Computer Aided Design of a series of inhibitors based on the knowledge of the TS active site. Several of these compounds have been put forward as target compounds for synthesis.
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Gustafsson, Jörgen. "Synthesis of cyclohexenedicarbaldehydes and studies of their biologic activity." Lund : Organic Chemistry 2, Lund Institute of Technology, University of Lund, 1994. http://books.google.com/books?id=ULpqAAAAMAAJ.
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Moorad, Razia. "Computer-aided drug design and the biological evaluation of anti-cancer drugs." Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/20715.
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Computer-aided drug design has become a promising alternative to high-throughput screening by identifying potential hits in silico for in vitro evaluation. In this study a combination of ligand-based and structure-based virtual screening was performed to identify in silico hits. This was based on finding similar inhibitors to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline, a potent inhibitor of the Nuclear Factor kappa B (NF-κB), a transcription factor that has a pivotal role in cancer survival and Pentamidine, an anti-parasitic drug that has recently been demonstrated to possess tumour-killing activity. A hierarchical methodology consisting of a similarity search followed by structure-based virtual screening of the ZINC database was performed. In order to perform the docking studies, binding sites for 6-amino-4-(4-phenoxyphenylethylamino) quinazoline on the NF-κB/IκBα complex were identified through blind docking. In addition, the National Cancer Institute (NCI) database was screened, utilising existing structure-activity relationship data from literature. A pharmacophore search was designed to test the hypothesis of the structural features necessary for activity as seen with quinazoline inhibitors of NF-κB. No virtual hits from the ZINC database were confirmed with in vitro activity. On the other hand, three compounds identified from the pharmacophore search were confirmed to inhibit cancer cell proliferation in vitro, with compound NSC727152 demonstrating the most potent activity. In order to determine if NSC727152 acted similarly to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline by inhibiting NF-κB, the effects of NSC727152 on the expression of NF-κB targeted genes, including the Growth Arrest and DNA Damage 45 (GADD45) α and γ and the Interleukin 6 (IL-6) genes were evaluated. GADD45 α and γ have been shown to be regulated by NF-κB during cancer progression and aberrant IL-6 gene expression has been implicated in cancer progression and mortality and its expression is at least partially mediated via constitutive activation of NF-κB. In this study, it has been demonstrated that GADD45 α and γ are upregulated after treatment with NSC727152. A down-regulation of the IL-6 promoter activity and mRNA expression in cancer cells treated with NSC727152 has also been demonstrated in this study. However, no hits similar to Pentamidine were confirmed with in vitro activity. In conclusion, the compound NSC727152 has been shown to inhibit NF-κB and further analysis is necessary to determine its full potential as an NF-κB inhibitor.
10
IACUZZI, VALENTINA. "Design of detection systems for the therapeutic drug monitoring of anticancer drugs." Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2967986.
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Considerato che la maggior parte dei farmaci antitumorali risulta caratterizzata da un'alta variabilità interindividuale nelle concentrazioni plasmatiche, che si riflette sull'efficacia del trattamento, durante il progetto di dottorato qui descritto sono state sviluppate tecniche per il loro monitoraggio terapeutico (TDM).
In primo luogo, è stato sviluppato, validato e cross-validato un metodo LC-MS/MS per la quantificazione di imatinib (IMA) e del suo metabolita attivo, norimatinib (norIMA), in pazienti affetti da tumore stromale gastrointestinale utilizzando la tecnica del dried blood spot (DBS). Il DBS consente di ridurre costi e tempi di campionamento e migliorare la compliance dei pazienti, poiché l’analisi viene effettuata tramite una goccia di sangue capillare depositata su carta. Da questa gli analiti vengono estratti con MeOH acidificato e l'estratto viene iniettato in un sistema LC (configurato con una cromatografia 2D per la pulizia on-line del campione), accoppiato ad un API-4000QT. Il metodo ha mostrato una buona linearità (R2> 0,996) nei range di 50-7500 ng/mL e 10-1500 ng/mL per IMA e norIMA. La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.1% e tra 88.9-112.8%, mentre quelle inter-day erano ≤6,6% e tra 95.7-104.3%, per entrambi gli analiti. Sono stati valutati inoltre: l'influenza dell'ematocrito (Hct), del volume depositato e dell'omogeneità del campione sull’analisi; la correlazione tra la concentrazione in DBS da prelievo venoso e da finger-prick (differenza tra -12 e 3.8%) e la stabilità dei DBSs (fino a 16 mesi). Il metodo è stato applicato per la quantificazione di 67 campioni DBSs di pazienti. Le concentrazioni in DBS, normalizzate per Hct e per un fattore di correzione che prescinde dall’Hct, correlano con quelle plasmatiche.
Parte del lavoro di questo progetto è stato anche dedicato allo sviluppo di strategie alternative a LC-MS/MS per favorire ulteriormente l’applicazione del TDM. In particolare, è stata eseguita la sintesi di polimeri (molecularly imprinted polymers - MIPs), con l'obiettivo futuro di applicarli come recettori in un sistema di rilevamento fluorimetrico per IMA. I MIPs sono stati sintetizzati sfruttando l'approccio non covalente e la polimerizzazione radicale ad alta diluizione. Tramite questa tecnica, i MIPs ottenuti, sintetizzati in DMSO e con acido metacrilico come monomero funzionale, presentano dimensioni nanometriche (dati acquisiti tramite dynamic light scattering). I tests di rebinding hanno dimostrato che solo 2 MIPs sono stati in grado di legare IMA con una buona specificità (rispetto ai corrispondenti polimeri non-imprinted) e selettività.
È stato infine sviluppato e validato un metodo LC-MS/MS per la quantificazione di ribociclib (RIBO), palbociclib (PALBO) e letrozolo (LETRO) in plasma. RIBO e PALBO sono farmaci appartenenti alla famiglia dei CDKIs recentemente approvati per il trattamento del carcinoma mammario in combinazione con LETRO. Il metodo messo a punto risulta adatto per l’applicazione nella pratica clinica, grazie ad una semplice preparazione del campione e ad una rapida analisi (6.5 min). Il metodo risulta lineare (R2 tra 0.992-0.983) nei range di concentrazione di 0.3-250 ng/mL per PALBO, 10-10000 ng/mL per RIBO e 0.5-500 ng/mL per LETRO (che coprono le concentrazioni plasmatiche terapeutiche). La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.6% e tra 94.5-112.3% per tutti e gli analiti, mentre quelle inter-day erano rispettivamente ≤7.3% e tra 94.5-112.9%. Il metodo è stato applicato con successo alla quantificazione di campioni plasmatici di pazienti.
In conclusione, con lo sviluppo di queste strategie si spera di implementare l’utilizzo del TDM per i farmaci oncologici nella pratica clinica.Despite the continuous progress in drug therapy, most anticancer drugs appear to be characterized by a high interindividual variability in plasma concentrations that is reflected in the efficacy of the treatment. From this arises the need of a personalized approach, so that the drug concentrations in plasma are adequate in each patient. On this basis, during the PhD project reported hereby, different techniques for therapeutic monitoring (TDM) of anticancer drugs were developed. First, a LC-MS/MS method for the quantification of imatinib (IMA) and its active metabolite, norimatinib (norIMA), was developed, validated and cross-validated in patients affected by gastrointestinal stromal tumour. This method allows to perform the quantification directly on a drop of capillary blood, exploiting the dried blood spot (DBS) technique, reducing sampling time, costs and improving patients’ compliance. Analytes were extracted from DBS samples by adding acidified methanol and the extract is injected into a LC system (configured with a 2D chromatography for online cleaning of the sample), coupled with an API-4000QT. The method showed good linearity (R2> 0.996) in the ranges of 50-7500 ng/mL and 10-1500 ng/mL for IMA and norIMA. Intra-day precision and accuracy were ≤3.1% and between 88.9-112.8%, respectively, while inter-day ones were ≤6.6% and between 95.7-104.3 %, for both analytes. Moreover, were also evaluated: the influence of the haematocrit (Hct), of the spot size and of the sample homogeneity on the analysis; the correlation between the concentration in DBS from venous sampling and from finger-prick (% difference between -12 and 3.8%) and the stability of DBSs (up to 16 months). Then, the method was applied for the quantification of 67 DBSs patients’ samples. Good agreement was obtained between IMA and norIMA concentrations found in DBS and plasma samples applying either the Hct normalization or avoiding it, simply multiplying the DBS concentration with a correction factor. Part of the work of this project was also dedicated for the development of alternative strategies for the quantification of anticancer drugs, to promote the application of TDM. In particular, the synthesis of molecularly imprinted polymers (MIPs) was performed, with the future goal of applying them as receptors in a fluorimetric detection system for IMA. MIPs were synthesized using the non-covalent approach and high dilution radical polymerization. Through this synthesis, the MIPs obtained, synthesized in DMSO with methacrylic acid as functional monomer, shown nanometric size (data acquired by dynamic light scattering). The rebinding tests then showed that 2 MIPs in particular were able to bind IMA with a good specificity (compared to the corresponding non-imprinted polymers) and selectivity. Finally, a LC-MS/MS method was developed and validated for the quantification of ribociclib (RIBO), palbociclib (PALBO) and letrozole (LETRO) in human plasma. RIBO and PALBO are drugs belonging to the CDKIs family, recently approved for breast cancer treatment in combination with LETRO. The method developed is suitable for its application in clinical practice, thanks to simple sample preparation and rapid analysis (6.5 min). The method showed a good linearity (R2 between 0.992-0.983) in the concentration ranges of 0.3-250 ng/mL for PALBO, 10-10000 ng mL for RIBO and 0.5-500 ng/mL for LETRO (covering the therapeutic plasma concentrations). Intra-day precision and accuracy were ≤3.6% and between 94.5-112.3% for all and analytes, respectively, while inter-day ones were ≤ 7.3% and 94.5-112.9%. The method has been successfully applied for patients’ plasma samples quantification. In conclusion, with the development of these strategies there is the hope to implement the application of TDM for anticancer drugs in the clinical practice.
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Mukherjee, Sreya. "Applications of Molecular Modelling and Structure Based Drug Design in Drug Discovery." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6331.
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Calcium ions have important roles in cellular processes including intracellular signaling, protein folding, enzyme activation and initiation of programmed cell death. Cells maintain low levels of calcium in their cytosol in order to regulate these processes. When activation of calcium-dependent processes is needed, cells can release calcium stored in the endoplasmic reticulum (ER) into the cytosol to initiate the processes. This can also initiate formation of plasma membrane channels that allow entry of additional calcium from the extracellular milieu. The change in calcium levels is referred to as calcium flux. A key protein involved in initiation of calcium flux is Stromal Interaction Molecule 1 (STIM1), which has recently been identified as a sensor of ER calcium levels. STIM1 is an ER transmembrane protein that is activated by a drop in ER calcium levels. Upon activation, STIM1 oligomerizes with a plasma membrane protein, ORA1, to form calcium-selective plasma membrane channels. Dysregulation of calcium flux has been reported in cancers, autoimmune diseases and other diseases. STIM1 is a promising target in drug discovery due to its key role early in calcium flux. Here we review the involvement and importance of STIM1 in diseases and we discuss STIM1 as a viable target for drug discovery using computational chemistry methods to rapidly identify new molecules to target STIM1. Herein, computational techniques were used to understand the mechanistic role of STIM1 and virtual screening is in process to discover potential inhibitors of STIM1 activity. Also mutational analysis on STIM1 was performed computationally to see the effect it had on the protein computationally.
It has been found that tumor cells and tissues, compared to normal cells, have higher levels of copper and possibly other metal ions. This presents a potential vulnerability of tumor cells that can serve as a physiological difference between cancer cells and normal cells and allows design of compounds that selectively target tumor cells while sparing normal cells. Recently we have identified compounds that have potential to inhibit the proteasome in tumor cells and induce cell death by mobilizing endogenous tumor copper resulting in in cellulo activation of the compound. These compounds hence act as pro-drugs, becoming active drugs in tumor cells with high copper content but remaining essentially inactive in normal cells, thereby greatly reducing adverse effects in patients. Such use would be of significant benefit in early detection and treatment of cancers, in particular, aggressive cancers such as pancreatic cancer which is usually not detected until it has reached an advanced stage. Six compounds were identified following virtual screening of the NCI Diversity Set with our proteasome computer model followed by confirmation with a biochemical assay that showed significant inhibition of the proteasome by the compounds in the presence of copper ions. In a dose response assay, NSC 37408 (6, 7-dihydroxy-1-benzofuran-3-one), our best compound, exhibited an IC50 of 3µM in the presence of 100 nM copper.
Chagas’ Disease, a parasitic disease caused by the parasite Trypanosma Cruzi, is endemic to Latin America. The disease manifests itself in a short acute phase and a long chronic phase. Current treatments are effective only in the acute phase and are not used in the chronic phase due to toxicity of the drugs. Hence a new drug discovery approach was chosen for this disease. Cruzain is the major etiologic enzyme involved in the disease and is only present in the parasite. It is also an enzyme expressed by the parasite in both phases. Herein, a novel peptoid library containing hydromethylketones was constructed and screened against a virtual structure of cruzain. The peptoids thus found through this drug discovery effort can be used as potential drug candidates against cruzain. Computational techniques will help achieve a high degree of specificity and aid in proposing assays for determining compounds with high activity
Alzheimer disease is the most common form of dementia. Its pathogenesis incorporates many potential targets for treatment. Among the targets identified, Apolipoprotein E4 (apoE4) is especially interesting due to its catalytic role in the degradation and clearance of amyloid beta (Aβ), a risk factor for Alzheimer disease. ApoE exists in 3 isoforms which directly impact its functionality in the body. There are characteristic structural differences between them. In ApoE4 ionic interactions exist between Arg-61 and Glu-255 residues, unlike the other isoforms. Hence interruption of this interaction by inhibitors may change the structure of apoE4 to a more linear structure as observed in the other isoforms. Virtual screening of the NCI diversity set on an energy minimized protein virtual structure was performed to identify potential small molecule inhibitors and to gain further understanding of interactions that can be targeted to inhibit this protein. From the top ligands in the NCI diversity set, a peptide library was designed to target the protein.
Previous research has indicated that liquid assisted grinding (LAG) is efficient and reliable for cocrystal formation when compared to solvent crystallization and dimethyl formamide is the best solvent for grinding. Herein, we report the comparison of four screening processes: Slurry, solvent crystallization, LAG and dry grinding. Thirty-eight crystal forms containing the Narom··· COOH, Narom···OH supramolecular heterosynthons were screened in the process, and it was observed that slurry methodology is as efficient and reliable in forming cocrystals as solution crystallization. Twenty-four new crystal forms were also isolated herein. LAG was found to be more efficient as compared to dry grinding and was successful in the formation of twenty-five crystal forms of the thirty-eight screened. Dimethyl formamide still remains the best solvent for LAG. All our slurry experiments were performed in water and it was found that water can be used reliably for this method for compounds within a wide range of solubility, thereby increasing the versatility and usability of this method for future screening procedures.
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Chieng, Heng Liang Norman, and n/a. "Amorphous drug preparation using ball milling." University of Otago. School of Pharmacy, 2008. http://adt.otago.ac.nz./public/adt-NZDU20081209.162001.
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Polymorphism and crystallinity are now recognised as important issues in drug development. This is shown by the increased amount of research in this area over recent years. In pharmaceutical development milling is an important unit operation for size reduction to improve powder handling, processing and dissolution rate. The aim of this thesis was to investigate the effect of ball milling (and cryo-milling) on the solid state properties, including amorphous drug formation, of pharmaceutical solids.
Milling was carried out using an oscillatory ball mill (Mixer Mill MM301, Retsch GmbH & Co., Germany). In cryo-milling the milling jars were immersed in liquid nitrogen for three min before milling. XRPD was used as the main technique to evaluate the milled samples. Ranitidine hydrochloride (RAN) and indomethacin (INDO) were the model drugs used in this study.
It was found that upon milling, RAN form 1 converts to RAN form 2 via an amorphous phase. A faster amorphization rate was observed when the crystalline samples were cryo-milled. Amorphous ranitidine hydrochloride was characterized to have a glass transition (T[g]) range of 13 to 30 �C and a crystallization exotherm (T[c]) between 30 and 65 �C. Conversion was found to occur faster when the temperature of the solid powder was greater than the T[c]. Under various storage conditions, similarly, crystallization of the amorphous phase mainly led to RAN form 2. However, some form 1 and amorphous phase was also detected on the XRPD diffractograms. Using partial least squares regression, the amount of solid form components in the ternary RAN mixtures were successfully quantified. RAN form 2 did not convert to form 1 under any milling (including cryo-milling) or storage conditions used in this study. Overall, RAN form 2 was found to be the thermodynamically stable form and the two (RAN) polymorphs are likely to be a monotropic pair.
In a co-milling study of INDO and RAN, the two crystalline drugs were successfully converted into a single amorphous phase after 60 min of co-milling in a cold room (4 �C). The T[g] range (26-44 �C) was also characterized for these mixtures. DRIFTS spectra of the co-milled amorphous samples indicated an interaction had occurred between the carboxylic acid carbonyl (HO-C=O) and benzonyl amide (NC=O) of the INDO molecule with the aci-nitro (C=NO₂) of RAN. Depending on the ratio of INDO to RAN, in general, the amorphous mixtures were stable at 4 �C after 30 days of storage. Crystallization was faster when the binary mixtures were stored at higher temperature or contained higher amounts of RAN in the mixture. Although XRPD and DRIFTS suggested an interaction between the two drugs, co-crystal formation was not observed between INDO and RAN.
Ball milling can be used to produce amorphous drug. The rate and extent of amorphization is dependent on the milling conditions. A faster rate of amorphization was observed when the crystalline drugs were cryo-milled. Amorphous drug formation can be made either alone or in combination with another crystalline drug. Amorphization could offer a significant improvement on the dissolution profile and the bioavailability of the poorly water soluble drug - indomethacin. Furthermore, ball milling can also be used to produce a homogenous mix between solids. The �goodmix� effect can be used for seed-induced crystallization or, when the XRPD or Raman data were combined with partial least squares regression, to create a reliable calibration model for quantitative analysis.
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Pan, Xiaolei. "THE SLC22 TRANSPORTER FAMILY: NOVEL INSIGHTS TO ROLES IN DRUG EFFICACY, DRUG-DRUG INTERACTIONS AND MOOD DISORDERS." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3983.
Full textAbstract:
Numerous studies have demonstrated the impact of organic cation (OCTs; SLC22 family) and anion transporters (OATs; SLC22 family) on the efficacy and safety of clinically important therapeutics. To be specific, OCTs and OATs have been identified as determinants for uptake into and secretion from enterocytes, hepatocytes and renal proximal tubular cells, and are frequent sites of drug-drug interaction (DDI). In addition, OCTs expressed in brain are components of the low-affinity, high capacity clearance pathway (uptake-2) for biogenic monoamine neurotransmitters. As a result, OCTs may represent novel targets for mood disorders.
The inhibitory effects of several therapeutic agents, designed drugs and novel compounds were assessed on the function of OCTs/Octs and OATs/Oats. Among these compounds, the anthraquinone rhein showed significant inhibition on hOATs. While the antituberculosis drug ethambutol, the herbal products matrine and oxymatrine, synthetic cathinones, and all quinazoline and guanidine compounds produced significant inhibition on hOCT activity with most IC50 values in the micro- and even nanomolar ranges.
Considering the clinically relevant unbound concentrations in biofluids, significant DDI potentials were found for rhein, ethambutol, matrine, oxymatrine and several synthetic cathinones affecting enterocytes, hepatocytes and/or proximal tubules. As hOCT2 and hOCT3 may participate in modulating neurotransmitter homeostasis in the CNS, these findings also suggested that the CNS pharmacological effects of synthetic cathinones, quinazoline and guanidine compounds might be due to their inhibitory effects on OCTs; although their impact may be limited solely to clearance of these compounds. Based upon their in vitro OCT/Oct inhibition profiles, three lead quinazoline and guanidine compounds were chosen for in vivo studies. Potent antidepressant-like effects of one lead hOCT-interacting compound (KEO-099) were re-confirmed in the tail suspension test. While in vivo results of the two newly identified hOCT-interacting lead compounds were somewhat less clear.
Finally, homology modeling and docking studies for hOCT3 identified key amino acid residues that might be involved in interaction between hOCT3 and small molecules. Subsequent experiments confirmed a competitive mode of interaction between MPP+ and lead compounds on hOCT3. Thus, preliminary analysis indicates our hOCT3 homology model can be used to support rational drug design and high-throughput screening of novel hOCT substrates/inhibitors.
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Durrant, Jacob Devin. "Computational drug design applied to neglected disease." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3404614.
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Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed June 7, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (leaves 213-239).
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Majewski, Maciej. "Implications of Structural Stability for Drug Design." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/671195.
Full textAbstract:
The relevance of structural stability in drug design has been shown by the use of DUck in virtual screening campaign, as reported previously. The method provides a fast and easy way to assess hydrogen bond-based structural stability of a complex. However, the cause and consequences of structural stability in molecular recognition remain unknown. DUck still has some limitations and requires previous knowledge about the system to be applied successfully.
GENERAL OBJECTIVE:
The general objective of this work is to deepen the knowledge of the role and origin of structural stability in molecular recognition and extend its applicability in drug design. We wanted to test DUck on a large and diverse set of protein-ligand complexes and apply it in a more general scenario without detailed knowledge about the simulated system.
DETAILED OBJECTIVES:
The specific objectives were the following:
1. Investigate the role of structural stability in biomolecular complexes:
• Perform a large-scale assessment of hydrogen bond based structural stability on a set of highly trustworthy structures of protein- ligand and protein-fragment complexes.
• Compare the binding patterns for different classes of proteins
• Investigate how robust hydrogen bonds are organised in complex’s structure.
• Draw useful conclusions for drug design.
• Explain the cause of structural stability.
2. Extend the applicability domain of Dynamic Undocking:
• Combine docking with rDock and post-docking evaluation of poses with DUck into binding mode prediction protocol.
• Test the protocol on the set of complexes of proteins with drug-like molecules and fragments.
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Ahrenstedt, Lage. "Drug Eluting Hydrogels : Design, Synthesis and Evaluation." Doctoral thesis, University of Cape Town, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-36503.
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Hydrogels have successfully proved themselves useful for drug delivery applications and several delivery routes have been developed over the years. The particular interest in this work was to design, synthesise and evaluate in situ forming drug eluting hydrogels, which have the potential to ameliorate the healing of cardiovascular diseases. With this aim the anti-inflammatory and immunosuppressant drugs rapamycin (Ra) and dexamethasone (Dex) were made water soluble by conjugation with polyethylene glycol (PEG). Ra was attached pendant from the terminal of PEGs while Dex was incorporated into dendritic structures grown from PEGs. These conjugates were further crosslinked into hydrogels by either conjugate or thiol-ene addition. The gel degradation was tuned to take between 5 and 27 days by using gel building block combinations that induced either 2 or 4 hydrolytically labile bonds per crosslink or by varying the number of crosslinking sites of the building blocks. The use of thiol-ene addition prolonged the degradation time nearly seven folded compared to conjugate addition as a more stable crosslink was formed. Two different formulations for gelling via conjugate addition were used (acrylate-thiol or vinyl sulphone-thiol) to deliver Ra, which was carried by either a 4- or 2-armed PEG. The elution kinetic for the respective gel formulation was of zero order during 15 and 19 days of gel degradation. In addition, Ra was PEGylated via esters, with a distance of either one or two carbons to a nearby thio-ether functionality. The difference in ester conjugation resulted in a slight but significant change in drug-PEG conjugate stability, which was mirrored by the increased time to reach the half amount of total drug elution; from 9.3 to 10.2 days and from 5.1 to 9.7 days for the two gel formulations, respectively. Dexamethasone was incorporated via an ester into dendrons of first and second generation pending from 2- and 4-armed PEGs at loadings of 2, 4 or 6 Dex molecules per carrier molecule. The resulting elution kinetic was of zero order during degradation periods of 5-27 days. Released Dex still possessed biological activity as determined by an in vitro cell assay. The novelties in this thesis are: (A) slow release of rapamycin obtained by covalent incorporation into hydrogels, (B) the use of unique PEG-based dendrimers to incorporate dexamethasone into a hydrogel and (C) zero order sustained release of dexamethasone at physiological pH.Hydrogeler har framgångsrikt visat sig användbara för att leverera läkemedel och ett flertal metoder har utvecklats de senaste 20 åren. Fokuset i den här avhandlingen ligger på att designa, framställa och utvärdera läkemedelsutsöndrande hydrogeler som spontanhärdar in situ, vilka har potential att förbättra läkningen efter kardiovaskulär sjukdom. Med det syftet gjordes de anti-inflammatoriska och immunsänkande läkemedlen rapamycin (Ra) och dexametason (Dex) vattenlösliga genom att konjugeras med polyetylenglygol (PEG). Ra fästes kovalent längst ut på PEGar medans Dex inkluderades i dendritiska strukturer vilka byggdes från ändpunkten av PEGar. De här konjugaten tvärbands till hydrogeler via antingen konjugerad addition eller radikal polymerisation. Nedbrytningen av gelerna trimmades till att ta mellan 5 och 27 dagar genom att använda kombinationer av gelbyggstenar som bildar antingen 2 eller 4 hydrolyserbara estrar per tvärbindning eller genom att variera antalet tvärbindningspunkter hos byggstenarna. Användandet av radikal polymerisation i sig ledde till att nedbrytningen av geler tog nära sju gånger längre tid jämfört med geler gjorda via konjugerad addition eftersom stabilare tvärbindningar då formas. Två olika kombinationer för härdning via konjugerad addition (akryl-tiol eller vinylsulfon-tiol) användes för att leverera Ra som bars av antingen en 4- eller 2-armad PEG. Utsöndringskinetiken av Ra för de två kombinationerna var av nollte ordningen under de 15 och 19 dagar som gelerna degraderade. Dessutom, Ra PEGylerades via estrar med ett avstånd på antingen ett eller två kol till en närliggande tioeter. Skillnaden i avstånd ledde till en liten men signifikant skillnad i stabiliteten hos Ra-PEG konjugaten, vilket speglades i den förlängda tiden att nå halva mängden av den totala läkemedelsutsöndringen; från 9.3 till 10.2 dagar och från 5.1 till 9.7 dagar för de två respektive gelkombinationerna. Dex kopplades in via en esterbindning till dendroner av första och andra generationen byggda från PEGar med 2 eller 4 armar, vilket resulterade i att 2, 4 eller 6 Dex levererades per bärarmolekyl. Dex eluerade med nollte ordningens kinetik under degraderingsperioder på mellan 5 och 27 dagar. Vidbehålllen biologisk aktivitet av eluerad Dex bekräftades genom cellexperiment in vitro. Nyheterna i den här avhandlingen består av: (A) kontrollerad utsöndring av rapamycin uppnådd genom kovalent inbindning till hydrogeler, (B) användandet av unika PEGbaserade dendrimerer för kovalent inbindning av dexametason till hydrogeler och (C) nollte ordningens utsöndring av dexametason vid fysiologiskt pH.
QC 20130204
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Jenvey, Michelle Catherine. "Structure led drug design for the pentraxins." Thesis, University of Southampton, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439382.
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Sousa, Helena Alexandra Soares Gama de. "Drug utilization studies: Focus on questionnaire design." Master's thesis, Faculdade de Medicina da Universidade do Porto, 2007. http://hdl.handle.net/10216/22094.
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Abdel-Ghany, Yasser S. "Osmotic processes as targets for drug design /." The Ohio State University, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487779439847767.
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Wei, Yaoming. "Peptide deformylase : characterization and antibacterial drug design /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu148819244742765.
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Lee, Jae Hwan. "DRUG DELIVERY MICRODEVICE: DESIGN, SIMULATION, AND EXPERIMENTS." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3100.
Full textAbstract:
Ocular diseases such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa require drug management in order to prevent blindness and affecting millions of adults in US and worldwide. There is an increasing need to develop devices for drug delivery to address ocular diseases. This research focused on an implantable ocular drug delivery device design, simulation and experiments with design requirements including constant diffusion rate, extended period of time operation, the smallest possible volume of device and reservoir. The drug delivery device concept uses micro-/nano-channels module embedded between top and bottom covers with a drug reservoir. Several microchannel design configurations were developed and simulated using commercial finite element software (ANSYS and COMSOL), with a goal to investigate how the microchannel dimensions affect the diffusion characteristics. In addition to design simulations, various microchannel configurations were fabricated on silicon wafer using photolithography techniques as well as 3D printing. Also, the top and bottom covers of the device were fabricated from PDMS through replica molding techniques. These fabricated microchannel design configurations along with top and bottom covers were all integrated into the device. Both single straight microchannels (nine different sizes of width and depth) as well as four micro-channel configurations were tested using citric acid (pH changes) and Brimonidine drug (concentration changes using the Ultra-Violet Visible Spectrophotometer) for their diffusion characteristics. Experiments were conducted to obtain the diffusion rates through various single micro-channels as well as micro-channel configurations using the change in pH neutral solution to verify the functionality and normalized diffusion rate of microchannels and configurations. The results of experimental data of diffusion rate were compared with those obtained from simulations, and a good agreement was found. The results showed the diffusion rate and the optimum size of microchannel in conjunction with the required drug release time. The results obtained also indicate that even though specific diffusion rates can be obtained but delivering the drug with constant amount needs a mechanism at the device outlet with some control mechanism. For future studies, this result may be used as a baseline for developing a microfabricated device that allows for accurate drug diffusion in many drug delivery applications.
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Palm, Apergi Caroline. "Design and evaluation of drug delivery vehicles." Doctoral thesis, Stockholm : Department of Neurochemistry, Stockholm university, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8256.
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Creighton, Christopher John. "Reagents and reactions for peptidomimetic drug design /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2000. http://wwwlib.umi.com/cr/ucsd/fullcit?p9970682.
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Wheate, Nial. "Pharmaceutical Drug Design, Formulation, Testing, and Use." Thesis, The University of Sydney, 2020. https://hdl.handle.net/2123/22097.
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This compilation of my research has been organised into nine different sections based on the sub-themes on my research into medicines. Section one deals principally with my research and impact into the examination of the interactions of multinuclear platinum-based chemotherapy drugs with their cellular target, DNA. Section two covers the design and synthesis of new drugs including multinuclear platinum drugs and a new drug class of platinum drugs based on phenanthroline. Section three details my investigation of macrocycles as potential delivery vehicles for drugs; in particular, the delivery applications of a family of macrocycles called cucurbit[n]urils, but also includes my research with n-cyclodextrins, calix[n]arenes, and pillar[n]arenes. Section four expands on the cucurbit[n]uril research describing my work on designing and developing cucurbit[n]uril-based pharmaceutical dosage formulations. Section five contains my research into the application of various nanoparticles as delivery systems for platinum-based drugs, including: dendrimer-polymer nanoparticles, metallic nanoparticles based on gold and iron oxide, carbon nanotubes, and DNA aptamers. Section six provides my published research on the clinical use of platinum drugs including an examination of the recommendations provided to clinicians and the extent to which platinum drugs continue to be used to treat human cancers. Section seven describes my research into the testing of pharmaceutical formulations and my published papers on the development of undergraduate classes for making and testing pharmaceutical formulations. Section eight is a collation of my published book chapters and review papers highlighting how these have made an impact in the area of medicines, and section nine provides details on my international patents for drug delivery inventions.
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Parrill, Abby Louise 1970. "Applications of artificial intelligence in drug design." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/290612.
Full textAbstract:
Computer-aided drug design is a rapidly growing area of research. The design process can proceed from two angles: either the three-dimensional structure of the biological target is known, or it is unknown. Thus the area of computer-aided drug design can be separated into a number of problems. One problem is determining the structure of a biomolecule from experimental data, as is done in chapter 2 for colominic acid polylactone. These studies determined that there are two helical structures consistent with spectral data A second problem is designing a ligand complementary to the three-dimensional structure of the target. Chapters 3 and 4 describe studies leading to the design and evaluation of neuraminidase inhibitors. These studies indicate that several inhibitors studied are competitive inhibitors of the enzyme with better binding affinities than the natural ligand. The final,and potentially most difficult problem, is to infer features about the biological target from compounds known to bind to that target. Chapters 5 and 6 describe model studies and implementation of CLEW, a program to learn rules relating structural features to biological function. Results indicate that learning based on topological features is a useful first iteration in determining the pharmacophore, or three-dimensional arrangement of functionality required for biological activity.
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Sousa, Helena Alexandra Soares Gama de. "Drug utilization studies: Focus on questionnaire design." Dissertação, Faculdade de Medicina da Universidade do Porto, 2007. http://hdl.handle.net/10216/22094.
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McCallum, Emma Clare. "Adaptive phase II clinical trial design using nonlinear dose-response models." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709013.
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Nyberg, Joakim. "Practical Optimal Experimental Design in Drug Development and Drug Treatment using Nonlinear Mixed Effects Models." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-160481.
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The cost of releasing a new drug on the market has increased rapidly in the last decade. The reasons for this increase vary with the drug, but the need to make correct decisions earlier in the drug development process and to maximize the information gained throughout the process is evident. Optimal experimental design (OD) describes the procedure of maximizing relevant information in drug development and drug treatment processes. While various optimization criteria can be considered in OD, the most common is to optimize the unknown model parameters for an upcoming study. To date, OD has mainly been used to optimize the independent variables, e.g. sample times, but it can be used for any design variable in a study. This thesis addresses the OD of multiple continuous or discrete design variables for nonlinear mixed effects models. The methodology for optimizing and the optimization of different types of models with either continuous or discrete data are presented and the benefits of OD for such models are shown. A software tool for optimizing these models in parallel is developed and three OD examples are demonstrated: 1) optimization of an intravenous glucose tolerance test resulting in a reduction in the number of samples by a third, 2) optimization of drug compound screening experiments resulting in the estimation of nonlinear kinetics and 3) an individual dose-finding study for the treatment of children with ciclosporin before kidney transplantation resulting in a reduction in the number of blood samples to ~27% of the original number and an 83% reduction in the study duration. This thesis uses examples and methodology to show that studies in drug development and drug treatment can be optimized using nonlinear mixed effects OD. This provides a tool than can lower the cost and increase the overall efficiency of drug development and drug treatment.
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Dolla, William Jacob Spenner Becker Bryan R. "Drug diffusion and structural design criteria for conventional and auxetic drug-eluting stents." Diss., UMK access, 2006.
Find full textAbstract:
Thesis (Ph. D.)--School of Computing and Engineering and Dept. of Chemistry. University of Missouri--Kansas City, 2006."A dissertation in engineering and chemistry." Advisor: Bryan R. Becker. Typescript. Vita. Description based on contents viewed Jan. 26, 2007; title from "catalog record" of the print edition. Includes bibliographical references (leaves 127-130). Online version of the print edition.
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Schreiber, Kimberly C. M. "Assay development for use in drug discovery against Bovine Trichomoniasis." Scholarly Commons, 2007. https://scholarlycommons.pacific.edu/uop_etds/650.
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Bovine trichomoniasis is a venereal disease that affects cattle. The causative agent of this disease is Tritrichomonas foetus, a flagellated protozoan. There is no current FDA approved treatment for this disease. The purpose of this study was to develop new compound screening assays that will make the discovery of new compounds faster and more accurate. The CellTiter-Glo Luminescent Cell Viability Assay, a high throughput screening (HTS) assay from Promega, was found to be as affective at measuring cytotoxicity as traditional assaying techniques. For the first time. preen florescent protein. a reporter gene used in cell viability assavs was successfully transformed into T. foetus for use in HTS systems. This study also identified new compounds that can potentially be used as new treatments for this disease.
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Sun, Jian. "Computer-aided drug design for influenza A virus." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B44205156.
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Skalic, Miha 1990. "Deep learning for drug design : modeling molecular shapes." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/667503.
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Designing novel drugs is a complex process which requires finding molecules in a vast chemical space that bind to a specific biomolecular target and have favorable physio-chemical properties. Machine learning methods can leverage previous data and use it for new predictions helping the processes of selection of molecule candidate without relying exclusively on experiments. Particularly, deep learning can be applied to extract complex patterns from simple representations. In this work we leverage deep learning to extract patterns from three-dimensional representations of molecules. We apply classification and regression models to predict bioactivity and binding affinity, respectively. Furthermore, we show that it is possible to predict ligand properties for a particular protein pocket. Finally, we employ deep generative modeling for compound design. Given a ligand shape we show that we can generate similar compounds, and given a protein pocket we can generate potentially binding compounds.El disseny de drogues novells es un procés complex que requereix trobar les molècules adequades, entre un gran ventall de possibilitats, que siguin capaces d’unir-se a la proteïna desitjada amb unes propietats fisicoquímiques favorables. Els mètodes d’aprenentatge automàtic ens serveixen per a aprofitar dades antigues sobre les molècules i utilitzar-les per a noves prediccions, ajudant en el procés de selecció de molècules potencials sense la necessitat exclusiva d’experiments. Particularment, l’aprenentatge profund pot sera plicat per a extreure patrons complexos a partir de representacions simples. En aquesta tesi utilitzem l’aprenentatge profund per a extreure patrons a partir de representacions tridimensionals de molècules. Apliquem models de classificació i regressió per a predir la bioactivitat i l’afinitat d’unió, respectivament. A més, demostrem que podem predir les propietats dels lligands per a una cavitat proteica determinada. Finalment, utilitzem un model generatiu profund per a disseny de compostos. Donada una forma d’un lligand demostrem que podem generar compostos similars i, donada una cavitat proteica, podem generar compostos que potencialment s’hi podràn unir.
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Ward, Richard. "Targeting inositol monophosphatase in structure-based drug design." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289291.
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Calabrò, Gaetano. "Accelerating molecular simulations : implication for rational drug design." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/16439.
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The development and approval of new drugs is an expensive process. The total cost for the approval of a new compound is on average 1.0 - 1.2 billion dollars and the entire process lasts about 12 - 15 years. The main difficulties are related to poor pharmacokinetics, lack of efficacy and unwanted side effects. These problems have naturally led to the question if new and alternative methodologies can be developed to find reliable and low cost alternatives to existing practices. Nowadays, computer-assisted tools are used to support the decision process along the early stages of the drug discovery path leading from the identification of a suitable biomolecular target to the design/optimization of drug-like molecules. This process includes assessments about target druggability, screening of molecular libraries and the optimization of lead compounds where new drug-like molecules able to bind with sufficiently affinity and specificity to a disease-involved protein are designed. Existing computational methods used by the pharmaceutical industry are usually focused on the screening of library compounds such as docking, chemoinformatics and other ligand-based methods to predict and improve binding affinities, but their reliable application requires improvements in accuracy. New quantitative methods based on molecular simulations of drug binding to a protein could greatly improve prospects for the reliable in-silico design of new potent drug candidates. A common parameter used by medicinal chemists to quantify the affinity between candidate ligands and a target protein is represented by the free energy of binding. However, despite the increased amount of structural information, predicting binding free energy is still a challenge and this technique has found limited use beyond academia. A major reason for limited adoption in the industry is that reliable computer models of drug binding to a protein must reproduce the change in molecular conformations of the drug and protein upon complex formation and this includes the correct modelling of weak non-covalent interactions such as hydrogen bonds, burials of hydrophobic surface areas, Van der Waals interactions, fixations of molecular degrees of freedom solvation/desolvation of polar groups and different entropy contributions related to the solvent and protein interactions. For several classes of proteins these phenomena are not easy to model and often require extremely computationally intensive simulations. The main goal of the thesis was to explore efficient ways of computing binding affinities by using molecular simulations. With this aim, novel software to compute relative binding free energies has been developed. The implementation is based on alchemical transformations and it extended a preexisted piece of software Sire, a molecular modeling framework, by using the OpenMM APIs to run fast molecular dynamics simulations on the latest GPGPU technology. This new piece of software has equipped the scientific community with a flexible and fast tool, not only to predict relative binding affinities, but also a starting point to develop new sampling methods for instance hybrid molecular dynamics and Monte Carlo. The implementation has been validated on the prediction of relative hydration free energy of small molecules, showing good agreement with experimental data. In addition, non-additive effects to binding affinities in series of congeneric Thrombin inhibitors were investigated. Although excellent agreement between predicted and experimental relative binding affinities was achieved, it was not possible to accurately predict the non-additivity levels in most of the examined inhibitors, thus suggesting that improved force fields are required to further advance the state-of-the art of the field.
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Jin, Albert Yongwon. "Biologically driven molecular modeling for anticonvulsant drug design." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0007/NQ42948.pdf.
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Sun, Jian, and 孙健. "Computer-aided drug design for influenza A virus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B44205156.
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Psaroudakis, G. "Virtual screening in drug design and model evaluation." Thesis, University of Essex, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422234.
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Fincham, Christopher I. "Replacement of peptidic amide bonds in drug design." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239080.
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Pavurala, Naresh. "Oral Drug Delivery -- Molecular Design and Transport Modeling." Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/53505.
Full textAbstract:
One of the major challenges faced by the pharmaceutical industry is to accelerate the product innovation process and reduce the time-to-market for new drug developments. This involves billions of dollars of investment due to the large amount of experimentation and validation processes involved. A computational modeling approach, which could explore the design space rapidly, reduce uncertainty and make better, faster and safer decisions, fits into the overall goal and complements the product development process. Our research focuses on the early preclinical stage of the drug development process involving lead selection, optimization and candidate identification steps. Our work helps in screening the most favorable candidates based on the biopharmaceutical and pharmacokinetic properties. This helps in precipitating early development failures in the early drug discovery and candidate selection processes and reduces the rate of late-stage failures, which is more expensive.
In our research, we successfully integrated two well-known models, namely the drug release model (dissolution model) with a drug transport model (compartmental absorption and transit (CAT) model) to predict the release, distribution, absorption and elimination of an oral drug through the gastrointestinal (GI) tract of the human body. In the CAT model, the GI tract is envisioned as a series of compartments, where each compartment is assumed to be a continuous stirred tank reactor (CSTR). We coupled the drug release model in the form of partial differential equations (PDE's) with the CAT model in the form of ordinary differential equations (ODE's). The developed model can also be used to design the drug tablet for target pharmacokinetic characteristics. The advantage of the suggested approach is that it includes the mechanism of drug release and also the properties of the polymer carrier into the model. The model is flexible and can be adapted based on the requirements of the clients. Through this model, we were also able to avoid depending on commercially available software which are very expensive.
In the drug discovery and development process, the tablet formulation (oral drug delivery) is an important step. The tablet consists of active pharmaceutical ingredient (API), excipients and polymer. A controlled release of drug from this tablet usually involves swelling of the polymer, forming a gel layer and diffusion of drug through the gel layer into the body. The polymer is mainly responsible for controlling the release rate (of the drug from the tablet), which would lead to a desired therapeutic effect on the body.
In our research, we also developed a molecular design strategy for generating molecular structures of polymer candidates with desired properties. Structure-property relationships and group contributions are used to estimate the polymer properties based on the polymer molecular structure, along with a computer aided technique to generate molecular structures of polymers having desired properties. In greater detail, we utilized group contribution models to estimate several desired polymer properties such as grass transition temperature (Tg), density (ρ) and linear expansion coefficient (α). We subsequently solved an optimization model, which generated molecular structures of polymers with desired property values. Some examples of new polymer repeat units are - [CONHCH₂ - CH₂NHCO]n -, - [CHOH - COO]n -. These repeat-units could potentially lead to novel polymers with interesting characteristics; a polymer chemist could further investigate these. We recognize the need to develop group contribution models for other polymer properties such as porosity of the polymer and diffusion coefficients of water and drug in the polymer, which are not currently available in literature.
The geometric characteristics and the make-up of the drug tablet have a large impact on the drug release profile in the GI tract. We are exploring the concept of tablet customization, namely designing the dosage form of the tablet based on a desired release profile. We proposed tablet configurations which could lead to desired release profiles such as constant or zero-order release, Gaussian release and pulsatile release. We expect our work to aid in the product innovation process.Ph. D.
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Niknezhad, Sepideh. "STRATEGIC DESIGN OF NANOFIBER CARRIERS FOR DRUG RELEASE." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1513257280368733.
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Rigden, Daniel. "Phosphofructokinase as a target for rational drug design." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/20753.
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There is a pressing need for new anti-parasitic drugs. Parasitic infection is an enormous, and growing, worldwide problem. Current treatments are generally ineffective and cause side-effects. Organisms resistant to some of the more effective drugs are appearing. A good target for drug intervention is glycolysis on which many parasites rely for their energy supply. Phosphofructokinase (PFK) is a good choice of glycolytic enzyme for targeting since it is belived to catalyse the major regulatory step of glycolysis. However, inhibition of parasite PFK must take place with as little inhibition of the host PFK as possible. The aim of this work was to tackle this problem of species selectivity. In the absence of much information about parasite PFKs, a model system was used which comprised two of the best-studied PFKs. The goal was inhibition of Escherichia coli PFK by compounds little affecting rabbit muscle PFK. Models of the structure for rabbit muscle PFK were built based on the justified assumption of a shared protein fold with Escherichia coli PFK. Several ligand design approaches were used. Some used protein structure information like the program LUDI. Database searches used information from the structures of known ligands. The question of species selectivity was addressed during the design process. Several classes of putative ligands were produced. These ranged from disparate organic componds suggested by LUDI to substrate analogs modelled using molecular mechanics procedures. Testing of putative ligands was by a variety of techniques such as enzymes assay fluorescence and protection against protein denaturation. Finally, the results were summarised and future prospects considered.
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Valsborg, Jacob Stenmann. "Design and synthesis of radioligands in drug development /." [Cph.] : Royal danish School of Pharmacy, Department of Medicinal Chemistry, 2002. http://www.dfh.dk/phd/defences/jacobvalsborg.htm.
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Lucato, Arianna <1991>. "Computational design of novel protein-drug delivery systems." Master's Degree Thesis, Università Ca' Foscari Venezia, 2019. http://hdl.handle.net/10579/16136.
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Cancer is one of the leading causes of death throughout the world and the number of cases per year is reported to rise to 23.6 million by 2030. Amongst the different types of treatments available, chemotherapy represent the most common one. Despite its proven capability of tumour shrinkage and prevention from coming back after surgery, several factors limit its potential. These include poor bioavailability and biodistribution of the majority of the chemotherapeutic agents commonly used, the high dose required, their numerous adverse side effects, the development of drug resistance and non-specific targeting.
To overcome these limitations, I propose to develop novel protein-based drug delivery system capable of selectively transporting large quantities of chemotherapeutics at the tumour-site thus conferring greater therapeutic indices and efficacy. The new systems are based on proteins, natural existing polymers, that have the intrinsic property of binding small molecules with high affinity and specificity.
The project is structured in two phases. In the first phase I applied FuncLib, an automated method that uses phylogenetic analysis and Rosetta design calculations, to design mutants with higher affinity toward two selected chemotherapeutic agents. In the second phase, fifty-five designs were selected according to G Rosetta energy score and structural diversity, synthesised and assembled using a repertoire of molecular biology techniques.
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Skarbek, Charles. "Synthèse et évaluation pharmacologique d’analogues préactivés de l’ifosfamide : prodrogues et nanoparticules à visée antitumorale." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS247/document.
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L’ifosfamide (IFO) et le cyclophosphamide (CPM) sont des oxazaphosphorines, prodrogues nécessitant une bioactivation pour être actif. Dans le cas de l’IFO, sa biotransformation conduit à une faible libération du composé hydroxylé actif accompagnée d’effets secondaires toxiques. Des analogues préactivés de l’IFO avec des chaines C1-C30 saturées ou non ont été développés, afin de contourner ces toxicités liées à la voie toxicogène du métabolisme. Dans le cadre de la stratégie de pharmacomodulation de l’IFO, l’évaluation cytotoxique de ces composés synthétisés a été réalisée in vitro sur des lignées cellulaires cancéreuses humaines. Une étude in vivo du Géranyloxy-IFO, un candidat potentiel, a démontré un meilleur profil pharmacocinétique pour le G-IFO comparativement à l’IFO. Ces analogues ont ensuite été vectorisés sous forme de nano-systèmes, soit par auto-assemblage ou par encapsulation lipidique constituant des vecteurs de 1ère génération. Ceux-ci continuent d’être développés afin de leur conférer une spécificité par ciblage passif ou actif.Par ailleurs, le CPM est connu pour son activité sur le système immunitaire à faible dose. Au vue de la proximité structurale entre l’IFO et el CPM, nous avons étudié l’effet immunomodulateur de l’IFO à faibles doses, en comparaison à la dose immunomodulatrice du CPM.La combinaison de ces deux stratégies (préactivation & effet immunomodulateur) pourrait conduire au développement de nouveaux dérivés démontrant une synergie antitumorale des effets antiprolifératif et immunomodulateur de ces oxazaphosphorinesIfosfamide (IFO) and cyclophosphamide (CPM) are oxazaphosphorines, prodrugs requiring bioactivation to be active. Regarding IFO, its biotransformation leads to a low release of the active hydroxylated compound with associated toxic side effects. Preactivated IFO analogs with saturated or unsaturated C1-C30 chains have been developed to circumvent these toxicities related to the toxicogenic pathway of metabolism. As part of IFO's pharmaco-modulation strategy, the cytotoxic evaluation of these compounds, synthesized by engraftment of poly-isoprenyloxy chains, was carried out in vitro on human cancer cell lines. In vivo study of the lead shows the better pharmacokinetic profile of Geranyloxy-IFO compared to IFO. These analogs were then vectorized as nanosystems, either by self-assembly or by lipidic encapsulation leading to 1st generation nanosystems. They are still under investigation in order to bring specificity by passive or active targeting.Furthermore, CPM is known for having an activity on the immune system at low dose. Due to the structural proximity of IFO and CPM, we fulfilled studies to highlight the effect of IFO on the immune system at low dose in comparison to the immunomodulatory dose of CPM.The combination of these two strategies (preactivation & immunomodulatory effect) could lead to the development of novel derivatives showing an antitumor synergy of the antiproliferative and immunomodulatory effects of these oxazaphosphorines
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Dale, L. D. "Studies of drug/DNA interactions in vitro." Thesis, Open University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234900.
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Murthy, Niren. "The design and synthesis of endosomal disruptive polymers /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/8113.
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Dube, Admire. "The design, preparation and evaluation of Artemisia Afra and placebos in tea bag dosage form suitable for use in clinical trials." Thesis, University of the Western Cape, 2006. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_2915_1188480959.
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Artemisia Afra, a popular South African traditional herbal medicine is commonly administered as a tea infusion of the leaves. However, clinical trials proving it safety and efficacy are lacking mainly due to the absence of good quality dosage forms and credible placebos for the plant. The objectives of this study were to prepare a standardized preparation of the plant leaves and freeze-dried aqueous extract powder of the leaves, in a tea bag dosage form and to design and prepare credible placebos for these plant materials.
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Tripathi, Ashutosh. "DEVELOPMENT OF HINT BASED COMPUTATIONAL TOOLS FOR DRUG DESIGN: APPLICATIONS IN THE DESIGN AND DEVELOPMENT OF NOVEL ANTI-CANCER AGENTS." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1866.
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The overall aim of the research is to develop a computational platform based on HINT paradigm for manipulating, predicting and analyzing biomacromolecular-ligand structure. A second synergistic goal is to apply the above methodology to design novel and potent anti-cancer agents. The crucial role of the microtubule in cell division has identified tubulin as an interesting target for the development of therapeutics for cancer. Pyrrole-containing molecules derived from nature have proven to be particularly useful as lead compounds for drug development. We have designed and developed a series of substituted pyrroles that inhibit growth and promote death of breast tumor cells at nM and μM concentrations in human breast tumor cell lines. In another project, stilbene analogs were designed and developed as microtubule depolymerizing agents that showed anti-leukemic activity. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of tubulin inhibitors that bind at the αβ-tubulin colchicine site. These studies coupled with HINT interaction analyses were able to describe the complex structure and the binding modes of inhibitors. Qualitative analyses of the results showed general agreement with the experimental in vitro biological activity for these derivatives. Consequently, we have been designing new analogs that can be synthesized and tested; we believe that these molecules will be highly selective against cancer cells with minimal toxicity to the host tissue. Another goal of our research is to develop computational tools for drug design. The development and implementation of a novel cavity detection algorithm is also reported and discussed. The algorithm named VICE (Vectorial Identification of Cavity Extents) utilizes HINT toolkit functions to identify and delineate a binding pocket in a protein. The program is based on geometric criteria and applies simple integer grid maps to delineate binding sites. The algorithm was extensively tested on a diverse set of proteins and detects binding pockets of different shapes and sizes. The study also implemented the computational titration algorithm to understand the complexity of ligand binding and protonation state in the active site of HIV-1 protease. The Computational titration algorithm is a powerful tool for understanding ligand binding in a complex biochemical environment and allows generating hypothesis on the best model for binding.
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Zephyr, Jacqueto. "Robust Drug Design Strategies and Discovery Targeting Viral Proteases." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1157.
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Viral proteases play crucial roles in the life cycle and maturation of many viruses by processing the viral polyprotein after translation and in some cases cleaving host proteins associated with the immune response. The essential role of viral proteases makes them attractive therapeutic targets. In this thesis, I provide an introductory summary of viral proteases, their structure, mechanism, and inhibition, while the breadth of this thesis focuses on the Hepatitis C virus (HCV) NS3/4A and Zika virus (ZIKV) NS2B/NS3 viral proteases.
HCV NS3/4A protease inhibitors (PIs) have become a mainstay in combination therapies. However, drug resistance remains a major problem against these PIs. In this thesis, I applied insights from the HCV substrate envelope (SE) model to develop strategies for designing PIs that are less susceptible to resistance. Also, I used the HCV NS3/4A protease as a model system to decipher the molecular mechanism and role of fluorination in HCV PIs potency and drug resistance. The drug design strategies described in this thesis have broad applications in drug design.
The ZIKV is an emerging global threat, and currently, with no treatment available. In this thesis, I described the discovery, biochemical and antiviral evaluation of novel noncompetitive quinoxaline-based inhibitors of the ZIKV NS2B/NS3 protease. The inhibitors are proposed to interfere with NS2 binding to NS3, thereby preventing the protease from adopting the closed and active conformation. The inhibitors from this work will serve as lead compounds for further inhibitor development toward the goal of developing antivirals.
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Al-Kassas, Raida. "Design of particulate delivery systems." Thesis, Queen's University Belfast, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239000.
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