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Pharmaceutics and Drug Design Commons™
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Articles 1 - 12 of 12
Full-Text Articles in Pharmaceutics and Drug Design
Protein Allostery Probed By Ligands Across Sites, Virgil A. Woods
Protein Allostery Probed By Ligands Across Sites, Virgil A. Woods
Dissertations, Theses, and Capstone Projects
Allostery is a pervasive regulatory principle throughout biology, yet the structural pathways by which distal inputs alter active‑site chemistry within protein structures remain incompletely defined and exploited. This dissertation uses protein tyrosine phosphatase 1B (PTP1B) as a tractable model to map those pathways with complementary experimental and computational tools. I integrate high‑resolution hydrogen-deuterium exchange mass spectrometry (HDX-MS), room-temperature crystallography, NMR, steady-state kinetics, crystallographic pseudo-ensembles, and machine-learning-guided ligand discovery. The working premise is that regulation reflects redistribution within a conformational ensemble rather than a binary switch. That orthogonal perturbations by small molecules, mutations, and protein partners can be used to both …
Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells, Ashley V. Huang, Yali Kong, Kan Wang, Milton L. Brown, David Mu
Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells, Ashley V. Huang, Yali Kong, Kan Wang, Milton L. Brown, David Mu
Department of Biomedical and Translational Sciences Faculty Publications
Breast cancer is one of the most common cancers globally. Unfortunately, many patients with breast cancer develop resistance to chemotherapy and tumor recurrence, which is primarily driven by breast cancer stem cells (BCSCs). BCSCs behave like stem cells and can self-renew and differentiate into mature tumor cells, enabling the cancer to regrow and metastasize. Key markers like CD44 and aldehyde dehydrogenase-1 (ALDH1), along with pathways like Wingless-related integration site (Wnt), Notch, and Hedgehog, are critical to regulating this stem-like behavior of BCSCs and, thus, are being investigated as targets for various new therapies. This review summarizes marker-dependent strategies for targeting …
Design, Synthesis, And Nmr-Guided Characterization Of A Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 From P. Aeruginosa, Samuel Taylor Moore
Design, Synthesis, And Nmr-Guided Characterization Of A Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 From P. Aeruginosa, Samuel Taylor Moore
Master's Theses
Multi-drug resistance poses a serious threat to future generations and historical antibiotic pipelines; consequently, the medical and economic burdens associated with treating multidrug-resistant bacteria are substantiated. In this context, P. aeruginosa (PA) emerges as one of the most significant healthcare challenges, being a leading cause of resistance-associated mortality worldwide. Despite modern efforts to combat these poor outcomes, drug-resistant cases continue to rise, and the need for novel antibiotic treatment is apparent. To this end, we investigated relevant resistance mechanisms and past antibiotic targets within PA, and in doing so, we identified relationships between peptidoglycan biology and a periplasmic protein, Inhibitor …
Review Of Mpges-1 Inhibitors Based On The Benzoxazole And Its Isostere Scaffold For The Treatment Of Inflammatory Diseases, Abdullah M. Alwagdani
Review Of Mpges-1 Inhibitors Based On The Benzoxazole And Its Isostere Scaffold For The Treatment Of Inflammatory Diseases, Abdullah M. Alwagdani
Longitudinal Scholar's Project
The vital role of the prostanoid pathway in inflammation, pain, cancer, Alzheimer’s and many other diseases has attracted the drug discovery community to discover targets for therapeutic development. Although existing non-steroidal anti-inflammatory drugs (NSAIDs) inhibiting cyclooxygenases (COX) are widely used, the side effects of these NSAIDs limit the ling time medication. Microsomal prostaglandin E synthase-1 (mPGES-1) is an attractive target that is overexpressed during inflammations, and it could be a safe alternative to NSAIDs for treating inflammatory diseases.Since the discovery of mPGES-1 in 1997, many inhibitors have been developed since 2001. Only a few compounds were able to make it …
Identification And Characterization Of Novel, Small Molecule Inhibitors Of Spermine Oxidase, Amelia Bryn Furbish
Identification And Characterization Of Novel, Small Molecule Inhibitors Of Spermine Oxidase, Amelia Bryn Furbish
MUSC Theses and Dissertations
The major intracellular polyamines spermine and spermidine are abundant endogenous compounds that are essential for cellular growth and development. Dysregulation of polyamine metabolism has been implicated as a key mechanism of injury across multiple forms of clinically challenging pathologies. Of the enzymes within the polyamine pathway, the catabolic enzyme spermine oxidase (SMOX) is of particular interest as it is subject to induction in response to infection, neuronal excitotoxicity, ischemia, and oxidative stress. In addition to the loss of radical scavenging capabilities associated with spermine depletion, catabolism of spermine by SMOX results in the production of toxic byproducts, including H2 …
Design And Synthesis Of Small Molecule Drugs For Cns Disorders, Kirsten T. Tolentino
Design And Synthesis Of Small Molecule Drugs For Cns Disorders, Kirsten T. Tolentino
Theses & Dissertations
Dopamine (DA) is an important neurotransmitter for the regulation and long-term function of the central nervous system (CNS). DA binds to Dopamine Receptors (DR) to stimulate or inhibit adenyl cyclase production to further elicit a pharmacological response. DRs were cloned, and it was determined that there are two families separated by their function and five total subtypes distinguished by their amino acid structure. The Dopamine 4 receptor (D4R) is the second least studied subtype but has high expression in the frontal cortex, amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, and thalamus. Dopamine signaling and transmission, especially in the …
Association Of Environmental Pollutants Exposure With Pulmonary Fibrosis: A Mini Review Of Molecular Mechanism Mediated, Soni Siswanto, Bantari W.K. Wardhani
Association Of Environmental Pollutants Exposure With Pulmonary Fibrosis: A Mini Review Of Molecular Mechanism Mediated, Soni Siswanto, Bantari W.K. Wardhani
Pharmaceutical Sciences and Research
Pulmonary fibrosis is a specific form of chronic progressive interstitial lung disease. Deposition of extracellular matrix, mainly collagen, is the pathogenic characteristic of pulmonary fibrosis. Many reports show that environmental pollutants, particularly asbestos, silica, mercury, cadmium, and benzo(a)pyrene, are contributed in the etiology of lung injury and a risk factor in the development of idiopathic pulmonary fibrosis (IPF) in humans. Based on its physicochemical properties, environmental pollutant-induced pulmonary fibrosis can be developed after a particular type or dose of exposure. To date, some studies have focused on variant pollutants that are induced. However, the molecular mechanism of various pollutants to …
Characterization Of Di-Aryl Urea Compounds Against Acute And Chronic Toxoplasma Gondii, Austin Sanford
Characterization Of Di-Aryl Urea Compounds Against Acute And Chronic Toxoplasma Gondii, Austin Sanford
Theses & Dissertations
Toxoplasma gondii is an obligate intracellular parasite that has infected nearly 60 million individuals in the United States alone. Acute infection causes ill effects to the fetus in utero when mothers are primarily infected, and to immunocompromised individuals. Chronic infection consists of quiescent tissue cysts located primarily in brain tissue and is capable of reverting back to the acute stage causing severe toxoplasma encephalitis in immunocompromised individuals. Current treatments for acute infection are lacking while there are no approved treatments for the clearance of chronic infection. The aim of this research was to evaluate a family of di-aryl urea compounds …
Pharmacological Characterization Of Novel Serotonin Transporter Inhibitors Identified Through Computational Structure-Based Virtual Screening, Michael Wasko
Electronic Theses and Dissertations
Depression is a mental health disorder affecting greater than 350 million people worldwide with roughly 7% of the United States population diagnosed as of 2017. The selective serotonin reuptake inhibitors (SSRIs) have been the mainstay of pharmacotherapies for depression for the last 40 years. The SSRIs target the serotonin transporter (SERT), a monoamine transporter (MAT) responsible for terminating serotonergic neurotransmission. The SSRIs are not perfect therapeutics and suffer from delayed response times, inconsistent efficacy among patients, and often produce intolerable side effects. Therefore, a strong need exists to develop new antidepressants that are more efficacious and have fewer adverse effects. …
Validation And Application Of A Novel Target-Based Whole-Cell Screen To Identify Antifungal Compounds, Christian Alexander Dejarnette
Validation And Application Of A Novel Target-Based Whole-Cell Screen To Identify Antifungal Compounds, Christian Alexander Dejarnette
Theses and Dissertations (ETD)
Traditional approaches to drug discovery are inefficient and have several key limitations that constrain our capacity to rapidly identify and develop novel experimental therapeutics. To address this, we have devised a second-generation target-based whole-cell screening assay based on the principles of competitive fitness, which can rapidly identify target-specific and physiologically-active compounds. Briefly, strains expressing high, intermediate, and low levels of a preselected target protein were constructed, tagged with spectrally distinct fluorescent proteins (FPs), and mixed together. The pooled strains were then grown in the presence of various small molecules, and the relative growth of each strain within the mixed culture …
In Vitro Metabolic Stability Study Of New Cyclen Based Antimalarial Drug Leads Using Rp-Hplc And Lc-Ms/Ms, Apoorva V. Rudraraju, Mohammad F. Hossain, Anjuli Shrestha, Prince N.A. Amoyaw, Babu L. Tekwani, M. O. Faruk Khan
In Vitro Metabolic Stability Study Of New Cyclen Based Antimalarial Drug Leads Using Rp-Hplc And Lc-Ms/Ms, Apoorva V. Rudraraju, Mohammad F. Hossain, Anjuli Shrestha, Prince N.A. Amoyaw, Babu L. Tekwani, M. O. Faruk Khan
Pharmaceutical Science and Research
Metabolic stability of the new antimalarial drug leads is determined using Human Liver Microsome (HLM) and specific cytochrome P450 enzyme (CYP2C8) taking the clinically used antimalarial drug chloroquine as a positive control. Experiment is done using standard methods. All the assays were conducted in 0.5 M phosphate buffer at pH 7.4. In general the metabolic reaction was initiated by adding 1 mM NADPH and 0.5 mg of enzyme. Incubations were done with time frequency of 0 hr, 1 hr, and 2 hrs at 37°C and the reactions were terminated by adding acetonitrile in the equal amounts of the assay mixture …
Phosphatidylinositol 3-Kinase (Pi3k) As A Therapeutic Target In Nsclc, Christopher W. Stamatkin
Phosphatidylinositol 3-Kinase (Pi3k) As A Therapeutic Target In Nsclc, Christopher W. Stamatkin
Theses and Dissertations--Pharmacy
Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using …