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Full-Text Articles in Medicine and Health Sciences
Computer-Aided Drug Discovery For Helicobacter Pylori, Nicole Ann Vita
Computer-Aided Drug Discovery For Helicobacter Pylori, Nicole Ann Vita
Theses and Dissertations (ETD)
Helicobacter pylori is a high-priority drug-resistant pathogen and is currently the only bacteria considered to be a class I carcinogen and there is a critical need to identify novel chemical matter to treat H. pylori infections. Hp is responsible for greater than 60% of gastric cancer related deaths and 89% of all gastric cancer morbidities. In a previous study, our lab identified novel Hp thienopyrmidine inhibitors that target respiratory complex I, an essential enzyme in respiration. Respiratory complex I is a large asymmetric multidomain and membrane bound enzyme and due to these innate features, it is not practical for biophysical …
Computational Studies And Design Of Pparγ And Glut1 Inhibitors, Suliman Almahmoud
Computational Studies And Design Of Pparγ And Glut1 Inhibitors, Suliman Almahmoud
Theses & Dissertations
The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. PPARγ is a target for insulin-sensitizing drugs, and it plays a significant function in prostate cancer. PPARγ antagonists have anti-proliferative effects in a broad range of hematopoietic and epithelial cell lines. The ligand binding domain (LBD) of PPARγ is large and has orthosteric and allosteric binding sites. Several PPARγ-ligand co-crystal structures show two bound molecules, one to the orthosteric pocket and a second to the allosteric …
Hit Identification For Pkcζ Inhibitors: Structure-Based Optimization, Virtual Screening, And Biological Evaluation, Xiaoxin Wu
Theses and Dissertations (ETD)
Protein kinase C ζ (PKCζ) is believed to be a promising target for the treatment of some diseases, including inflammatory diseases, obesity and diabetes. Hit identification of PKCζ inhibitors was conducted by structure-based modification, virtual screening and biological evaluation. Among all the compounds selected and synthesized, compound JW-1-60A showed moderate activity against PKCζ at 30 μM and 100 μM. The molecular modeling studies showed that the binding mode of JW-1-61A was very close to the binding mode of JP-3-149, a reported PKCζ inhibitor with very potent activity, which might partially explain the moderate activity of JW-1-61A. Based on the structure …
Targeting Protein Kinases To Manage Or Prevent Alzheimer’S Disease, Manal A. Nael
Targeting Protein Kinases To Manage Or Prevent Alzheimer’S Disease, Manal A. Nael
Electronic Theses and Dissertations
Due to the pressing need for new disease-modifying drugs for Alzheimer’s disease (AD), new treatment strategies and alternative drug targets are currently being heavily researched. One such strategy is to modulate protein kinases such as cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase-3 (GSK-3α and GSK-3β), and the protein kinase RNA-like endoplasmic reticulum kinase (PERK). AD intervention by reduction of amyloid beta (Aβ) levels is also possible through development of protein kinase C-epsilon (PKC-ϵ) activators to recover α-secretase levels and decrease toxic Aβ levels, thereby restoring synaptogenesis and cognitive function. In this way, we aim to develop …
Molecular Modeling And Sar Studies Of Cdk5/P25 Selective Inhibitors, Arindam Chatterjee
Molecular Modeling And Sar Studies Of Cdk5/P25 Selective Inhibitors, Arindam Chatterjee
Electronic Theses and Dissertations
Alzheimer's disease (AD) is one of the most dreaded forms of progressive neurodegenerative diseases. The two main hallmarks of AD are the formation of amyloid senile plaques and neurofibrillary tangles. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase, which expressed primarily in the central nervous system. In the biochemical process the CDK5-natural activator, p35 is cleaved by calpain to a shorter protein p25, which in turn hyperphosphorylates Tau, forms neurofibrillary tangles and causes AD. CDK5 deregulation is also indicated in other neurodegenerative diseases, such as Huntington's chorea, stroke, Parkinson's disease, amyotrophic lateral sclerosis, major depression and substance …
Scaffold Perception, Compharmacophore Model Development, And Quantitative Structure-Affinity Relationships Of Sigma Site Ligands, David Enos Watson
Scaffold Perception, Compharmacophore Model Development, And Quantitative Structure-Affinity Relationships Of Sigma Site Ligands, David Enos Watson
Electronic Theses and Dissertations
Sigma receptors are endogenous proteins with potential utility in treating psychological disorders, ischemia, the psychological and convulsive effects of drugs of abuse, and as an imaging agent for cancerous tissues, among others. Drug design efforts targeting these receptors have been hindered by a lack of structural information of the receptors themselves. Traditional ligand-based approaches have succeeded in generating many compounds with high affinity, and quite a few with selectivity for σ-1 receptors. There are few selective ligands for use as pharmacological probes for the σ-2 receptor. Much effort has gone into exploring the structure activity relationships of ligands targeting these …
Discovery Of Novel Glycogen Synthase Kinase-3beta Inhibitors: Molecular Modeling, Virtual Screening, And Biological Evaluation, Gang Fu
Electronic Theses and Dissertations
Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which is engaged in a variety of signaling pathways, regulating a wide range of cellular processes. Due to its distinct regulation mechanism and unique substrate specificity in the molecular pathogenesis of human diseases, GSK-3 is one of the most attractive therapeutic targets for the unmet treatment of pathologies, including type-II diabetes, cancers, inflammation, and neurodegenerative disease. Recent advances in drug discovery targeting GSK-3 involved extensive computational modeling techniques. Both ligand/structure-based approaches have been well explored to design ATP-competitive inhibitors. Molecular modeling plus dynamics simulations can provide insight into the protein-substrate …
Use Of Structure-And Ligand-Based Drug Design Tools For The Discovery Of Small Molecule Inhibitors Of Cysteine Proteases For The Treatment Of Malaria And Sars Infection, Falgun Shah
Electronic Theses and Dissertations
A wide array of molecular modeling tools were utilized to design and develop inhibitors against cysteine protease of P. Falciparum Malaria and Severe Acute Respiratory Syndrome (SARS). A number of potent inhibitors were developed against cysteine protease and hemoglobinase of P. falciparum , referred as Falcipains (FPs), by the structure-based virtual screening of the focused libraries enriched in soft-electrophiles containing compounds. Twenty one diverse, non-peptidic, low micromolar hits were identified. A combined data mining and combinatorial library synthesis approach was performed to discover analogs of virtual screening hits and establish the structure-activity relationships (SAR). However, the resulting SAR of the …
Development And Applications Of The Hint Forcefield In Prediction Of Antibiotic Efflux And Virtual Screening For Antivirals, Aurijit Sarkar
Development And Applications Of The Hint Forcefield In Prediction Of Antibiotic Efflux And Virtual Screening For Antivirals, Aurijit Sarkar
Theses and Dissertations
This work was aimed at developing novel tools that utilize HINT, an empirical forcefield capable of quantitating both hydrophobic and hydrophilic (hydropathic) interactions, for implementation in theoretical biology and drug discovery/design. The role of hydrophobicity in determination of macromolecular structure and formation of complexes in biological molecules is undeniable and has been the subject of research across several decades. Hydrophobicity is introduced, with a review of its history and contemporary theories. This is followed by a description of various methods that quantify this all-pervading phenomenon and their use in protein folding and contemporary drug design projects – including a detailed …
Structure- And Ligand-Based Design Of Novel Antimicrobial Agents, Kirk Edward Hevener
Structure- And Ligand-Based Design Of Novel Antimicrobial Agents, Kirk Edward Hevener
Theses and Dissertations (ETD)
The use of computer based techniques in the design of novel therapeutic agents is a rapidly emerging field. Although the drug-design techniques utilized by Computational Medicinal Chemists vary greatly, they can roughly be classified into structure-based and ligand-based approaches. Structure-based methods utilize a solved structure of the design target, protein or DNA, usually obtained by X-ray or NMR methods to design or improve compounds with activity against the target. Ligand-based methods use active compounds with known affinity for a target that may yet be unresolved. These methods include Pharmacophore-based searching for novel active compounds or Quantitative Structure-Activity Relationship (QSAR) studies. …