Medicine and Health Sciences Commons^™

Potent And Selective Small Molecule Mcl-1 Inhibitor Demonstrates Anti-Myeloma Activity And Overcomes Chemotherapy Resistance, Omar Sami Faleh Al-Odat

Theses and Dissertations

Despite a record number of clinical studies investigating various anti-myeloma treatments, the 5-year survival rate for multiple myeloma (MM) patients in the US is only 55%, and nearly all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive” which means they can adapt and evolve following treatment. Thus, new therapeutic approaches to combat survival mechanisms and target treatment resistance are required. Importantly, Mcl-1, anti-apoptotic protein, is required for the development of MM and treatment resistance. This study looks at the possibility of KS18, a selective Mcl-1 inhibitor, to treat MM and overcome resistance. Our investigation demonstrates …

Behavioral Effects Of Novel Treatments For Pain Using Different Pathways, Danya M I Aldaghma

Theses and Dissertations

Pain is defined as an unpleasant sensation that is mostly caused by a stimulus from our surroundings. This sensation has the potential to become a significant concern, disrupting daily activities, and diminishing overall quality of life. However, it could also hold significant importance as it serves as a protective mechanism. Pain acts as an alarm system for the human body, alerting it to potentially harmful situations where tissues may be at risk of damage1. Despite the considerable advancements in pain treatment and the extensive knowledge scientists possess regarding the pathophysiology and pathways of pain, numerous medications aimed at alleviating pain …

Design And Synthesis Of Substituted N,3,3-Triphenylpropanamide And 1-Benzhydryl-N-Phenylazetidine-3-Carboxamide Analogs And Their Biological Evaluation, Michael Dorogan

Theses and Dissertations

As D₁R agonism has significant implications in the treatment of cognitive deficits, we sought to develop novel D₁R PAMs, through the derigidification of BMS D₁R PAM hit compound. While we were able to synthesize derigidified analogs of the BMS hit compound, derigidification did not produce active D₁R ligands.

Assessing Drug Development Proporties Of Antithrombotic And Anti - Cancer Agents, Elsamani I. Abdelfadiel

Theses and Dissertations

The current GAG anticoagulants such as heparin, heparin derivatives, and vitamin K antagonists, such as warfarin continue to be the backbone of anticoagulant therapy. These drugs act through an indirect mechanism to convey inhibition of several coagulation enzymes. However, xv their use leads to several serious adverse effects, such as excessive bleeding risk and unpredictability of patient response. Regardless of their clinical achievement, every individual agent is accompanied by several side effects, particularly major/minor bleeding, thrombocytopenia, drug-food or drug-drug interactions, or absence of antidote. Of all these side effects, bleeding, and a lack of an effective antidote to reverse excessive …

Structure-Based Drug Discovery And Development Of Protein Structure Prediction Tools Using An Empirical Force Field, Noah B. Herrington

Theses and Dissertations

Traditional drug discovery has rapidly accelerated thanks to development of computational molecular modeling. The crucial component that these computational studies hinge upon is having a well-defined, and energetically favorable structure. Structures of proteins and ligands that meet these criteria are important for accurately simulating models used to study drug binding. To demonstrate the role of accurate structure simulation in the study of these events, this thesis presents, first, a story examining the problem of accurate structure modeling of ionizable residues within protein structures, specifically aspartic acid, glutamic acid, and histidine. I present our method, which uses the HINT force field …

Examining Ayahuasca Constituents At 5-Ht2a Receptors In Search Of Antidepressant Action, Jeremy D. Rolquin

Theses and Dissertations

Recently, it has been reported that ligands of the 5-HT_2A receptor can have drastic and fast-acting efficacy towards a number of different mental health disorders, such as depression and anxiety. A mixture of Amazonian plants calledayahuasca contains multiple compounds which have been shown to interact with the serotonergic system, and the 5-HT_2Areceptor in particular.

The structurally similar compounds (DMT, harmine, harmaline, and tetrahydroharmine) found in ayahuasca were examined for differences in their physiochemical properties that might contribute to their binding affinity for the 5-HT_2Areceptor. 3D Molecular modeling and docking studies of these compounds were …

Protein Structure And Interaction: The Role Of Aromatic Residues In Protein Structure And Interactions Between Pyridoxine 5'-Phosphate Oxidase/Dopa Decarboxylase, Mohammed H. Al Mughram

Theses and Dissertations

Naturally developed proteins are capable of carrying out a wide variety of molecular functions due to their highly precise three-dimensional structures, which are determined by their genetically encoded sequences of amino acids. A thorough knowledge of protein structures and interactions at the atomic level will enable researchers to get a deep foundational understanding of the molecular interactions and enzymatic processes required for cells, resulting in more effective therapeutic interventions. This dissertation intends to use structural knowledge from solved protein structures for two distinct objectives.

In the first project, we conducted a bioinformatics structural analysis of experimental protein structures using our …

Fabrication And Comparative Study Of Horizontal And Vertical Electrospun Protein-Polysaccharide Nanofiber Biomaterials, Ashley Rivera-Galleti

Theses and Dissertations

The use of biocompatible and biodegradable composite materials for biomedical applications has attracted the attention of many researchers in the past few years. In this study, we fabricated nanofibers of silk fibroin and cellulose and its derivatives to amalgamate their unique properties into a single material. The production of these nanofibers via electrospinning is of particular interest, and whereas several studies have been done on normal nanofibers, the formation of branched nanofibers is an exciting area not currently explored. Blend solutions are formed by dissolving silk and cellulose/cellulose acetate in formic acid separately and mixing to achieve the desired ratios. …

Investigation Of The Role Of Hydrophobic Amino Acids On The Structure-Activity Relationship In Ponericin L1 From Neoponera Goeldii, Nicholas Patrick Schifano

Theses and Dissertations

Due to the increase prevalence of antimicrobial resistance (AMR) antibiotic alternatives have been of great interest. Antimicrobial peptides (AMPs) and polymers like polymethacrylates that mimic AMPs are two non-traditional antimicrobial agents that have been investigated thoroughly over the years as a potential solution to the AMR problem. This study will further the understanding of the L1 peptide by investigating the role hydrophobic amino acids have on the antimicrobial activity. Biophysical and microbiological techniques were utilized to show that the L1 hydrophobic derivative showed enhanced binding to anionic lipid bilayers while maintaining low hemolytic activity. This study also elucidates the effect …

Endeavors Toward Novel Synthetic Roadmaps In The Synthesis Of Pertinent Pharmacological Molecular Scaffold Moieties, Justin David Horgan

Theses and Dissertations

One of the main goals in the GML lab group is the development of novel, economical, and environmentally friendly organic methods for the synthesis of pharmacologically relevant molecular moieties. The most salient pieces of data to the GML lab group members, reading dependable organic journals, are finding organic moieties that are largely unexplored, finding organic moieties which various research groups are having difficulty synthesizing, and finding complex organic procedures to key organic structures that can be easily reduced, or reconstructed, into novel methods that are more economical and environmentally friendly. By looking at these unexplored molecules, as well as hard …

The Exploration Of Novel Synthetic Methods Of Biologically Relevant Nitrogen And Halogen Containing Molecules, Rebekah Erin Strong

Theses and Dissertations

Visible light has become a highly useful, and regarded, tool to the organic chemist. The additions and transformations of an abundance of molecules can be achieved with the use of visible light and photocatalysts, when appropriate. More specifically compounds that contain nitrogen, halogens, or both are highly useful structures in nearly every chemical industry. They are elements found in naturally occurring molecules and have the capacity to mimic biologically active and relevant structures. This makes them useful targets for pharmaceutical compounds. Bromine and chlorine can act as leaving groups; this property makes molecules with these elements reactive and thus able …

Computational Study Of Drug Interactions Of Receptors, Specifically Glycoprotein D Of Human Herpes Virus 1 And Dopamine D4 Receptor, Griffin Fountain

Theses and Dissertations

This thesis introduces computer-aided drug design methods in Chapter 1 and discuss their applications on two receptors in Chapters 2 and 3: Glycoprotein D (gD) of Herpes Simplex Virus 1 (HSV-1) and Dopamine Receptor D4 (DRD4). The Herpes Simplex Virus is a human pathogen that develops unpleasant cold sores around the body, most commonly around the mouth, neck or genitals area. Currently there is no cure or vaccine that can eliminate this virus. Glycoprotein D (gD) is a viral ligand for host cell receptors such as nectin -1. This interaction mediates the entry of HSV-1. In chapter 2, we used …

Behavioral Analysis Of Conditions And Treatments Affecting Movement And Nociception, Indu Mithra Madhuranthakam

Theses and Dissertations

This thesis work includes three projects. First part deals with the investigation of novel D2 receptor ligands in Prepulse inhibition. The goal of this study is to establish a relationship between dopamine receptor antagonists and agonists and prepulse inhibition which can then serve as a working model for an in-vivo efficacy of novel dopamine D2 drugs. The second part of the thesis work deals with Niemann pick disease type C. Niemann pick disease type C is a progressive genetic disorder that is characterized by the lysosomal accumulation of lipids which causes neurodegeneration, dementia, ataxia, and death. NPC1_nmf164 mutant mice …

Efforts Toward Novel Methods For The Synthesis Of Stereochemically-Dense Pharmacologically Relevant Scaffolds, Lauren Nicole Tumbelty

Theses and Dissertations

Nitrogen is the most common pure element, present in nearly all relevant chemical compounds. It is an essential component of the building blocks of life such as proteins, nucleic acids, amino acids and adenosine tri-phosphate. There is a naturally occurring exchange between living organisms and the atmosphere which begins with the process of fixation. Although nitrogen is naturally abundant, the strength of the triple bond in atmospheric nitrogen prevents its applicability in organic synthesis. Therefore, the development of methods to place synthetic nitrogen into heteroatomic compounds plays an important role in the development of pharmacologically relevant scaffolds. Contained within this …

Bisphosohoglycertae Mutase: A Potential Target For Sickle Cell Disease, Anfal S. Aljahdali

Theses and Dissertations

Bisphosphoglycerate mutase (BPGM) is a part of the erythrocyte glycolysis system. Specifically, it is a central enzyme in the Rapoport-Leubering pathway, a side glycolytic pathway involved in the regulation of the concentration of the natural allosteric effector of hemoglobin (Hb), 2,3-bisphosphoglycerate (2,3-BPG). BPGM catalyses the synthesis and hydrolysis of 2,3-BPG through its synthase and phosphatase activities. The synthase activity is the main role of BPGM, while the phosphatase activity is low and is activated by the physiological effector, 2-phosphoglycolate (2-PG) with the latter mechanism poorly understood.

BPGM activity and 2,3-BPG levels in red blood cells (RBCs) have a significant role …

Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer

Theses and Dissertations

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …

Exploring The Dopamine Transporter Utilizing A Two-Pronged Approach With Novel Cathinone Analogs And Mutant Dopamine Transporters, Charles B. Jones Iii

Theses and Dissertations

The dopamine transporter (DAT) is responsible for the removal of the neurotransmitter from the synaptic gap and a therapeutic target for a multitude of drugs. While the ortholog Drosophila melanogaster dopamine transporter (dDAT) and human serotonin transporter (hSERT) have resolved structures, the human dopamine transporter (hDAT) does not. A 3-D computational homology model of hDAT was constructed for the study of molecular interactions with agents within the central binding site (S1) of the transporter.

Synthetic cathiones are a class of abused stimulant drugs that primarily target DAT. Greater than 150 cathinones have been identified on the clandestine market but there …

Development Of Sam-Based Chemical Probes For Methyltransferases, Daniel V. Mongeluzi

Theses and Dissertations

Fig.1. SAM analog for the profiling of MTase activity. A. Chemical structure of probe 1; B. General scheme of the labeling and capture strategy.

A

B

Methylation is a fundamental mechanism used in the biological system to modify the structure and function of biomolecules such as proteins, DNA, RNA, and metabolites.¹ Methyl groups are installed by a large and diverse class of S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTases), which transfer the sulfonium methyl group of SAM to either carbon, nitrogen, oxygen, or other heteroatoms on biomolecules.² Dysregulated MTase activity contributes to numerous diseases, including cancer, metabolic disorders, neurodegenerative diseases. …

Investigation Of The Sequence-Structure-Activity Relationship In Ponericin L1 From Neoponera Goeldii & Synergistic Interactions Of Ionic Liquids And Antimicrobials To Improve Efficacy, Alexandria S. Senetra

Theses and Dissertations

Non-traditional antimicrobials have been an area of great interest due to the increasing prevalence of antimicrobial resistance (AMR) in bacteria. Antimicrobial peptides (AMPs) & ionic liquids (ILs) are two examples that have been investigated as a potential solution. Most AMPs are naturally derived & exhibit high selectivity against bacterial targets over host cells. The venom-derived peptide, ponericin L1 from Neoponera goeldii, was used to investigate the role of cationic residues & net charge on peptide activity. Using both in vitro & microbiological methods, L1 peptide & derivatives exhibited an alpha-helical conformation with enhanced binding to lipid vesicles containing anionic lipids …

Searching For New Medications For The Treatment Of Alcohol Use Disorder, Harley M. Buechler

Theses and Dissertations

Alcohol use disorder (AUD) affects more than 15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. In this study, the effects of the D4 receptor antagonist, L-745,870, and the CB1 negative allosteric modulator, PSNCBAM-1, were both tested for effects in ethanol conditioned place preference (CPP) and oral ethanol self-administration. Food-restricted adult male mice were trained in operant chambers to nose poke for delivery of rewards, trained on ascending concentrations of alcohol with descending concentrations of Ensure and water, until the mixture self-administered was 8% …

Searching For New Analgesics Without Addiction Risks, Mohammad Atiqur Rahman

Theses and Dissertations

Opioids are widely used to treat acute and chronic pain. But opioid addiction to these compounds can cause social and life-threatening health problems, including the risk of overdose. In this thesis, I evaluated IBNtxA (3-iodobenzoyl naltrexamine), a novel mu opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone, in drug discrimination studies in order to better understand its subjective effects and more thoroughly its abuse liability. IBNtxA represents an intriguing lead compound for preclinical drug development specifically targeting MOR splice variants, potentially creating effective analgesics with reduced side effects. These results indicate that IBNtxA produces potent antinociception …

Synthesizing Modified Polymeric Nanoparticles For Biofilm Inhibition, Antibiotic Encapsulation, And Specific Targeting Against Pseudomonas Aeruginosa, Logan Schnorbus

Theses and Dissertations

Widespread usage of antibiotics is a growing concern due to antibiotic resistance development in bacteria. This is due to common use of antibiotics in agricultural, livestock, and clinical usage. Antibiotic resistance is developing at a rate in which it is outpacing new drugs on the market. New strategies in drug development are necessary to combat the increasing resistance. We designed several motifs of sugar-modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is an opportunistic pathogenic bacterium that is responsible for common life-threatening infection in hospitals. This gram-negative opportunistic pathogenic bacterium infects hosts with compromised immune systems …

An In Silico Study Of Small Molecule Anti-Cancer Agents Targeting Dna G-Quadruplexes, Holli-Joi Sullivan

Theses and Dissertations

Free ligand binding molecular dynamic simulations are a powerful tool used to probe the ligand binding process, mechanism and pathway and the insight gained can help expedite the early stages of drug discovery. Using these methods, we model the binding of two small molecule anti-cancer agents BRACO19 and CX-5461 to a variety of DNA G-quadruplexes (G4s) and a DNA Duplex. The first study focuses on the binding of BRACO19 to three different topological folds (parallel, anti-parallel and hybrid) of the human telomeric G4s. Our detailed analysis identified the most stable binding modes were end stacking and groove binding for the …

Development Of A Screening Assay For Type Iii Secretion System Inhibitors And High Throughput Screening Campaign Of Inhibitors Of Prp Of Staphylococcus Aureus, Heather A. Pendergrass

Theses and Dissertations

Antibiotics inhibit the growth or survival of bacteria by targeting their essential functions.¹ Due to weaknesses in traditional antibiotics and the increasing prevalence of antibiotic resistance genes, virulence factors are being targeted for therapeutic treatment of bacterial infection.² We have developed an assay to quantify and observe type III secretion system (T3SS) activity. The type III secretion system (T3SS) is a virulence factor present in some Gram-negative pathogens including enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC, respectively),³ and others.^4–9 The T3SS between EPEC and EHEC are highly conserved and share over 90% sequence identity with …

Synthesizing Galactose Modified Polymeric Nanoparticles For Biofilm Inhibition Of Pseudomonas Aeruginosa, Tyler R. Flockton

Theses and Dissertations

Treating patients with antibiotics is becoming harder with the increase in antibiotic resistance. This is due to the widespread antibiotic use in clinical and agricultural settings. With antibiotic resistance outpacing new drugs making it to the market, developing new options to treat bacterial infections is and will be important. We created sugar modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is a gram-negative opportunistic pathogen that infects its host that has a compromised immune system. This makes it one of the most significant bacterial infection in hospitals. P. aeruginosa uses biofilms as an attack mechanism …

Synthesis Of Betulinic Acid Via Baylis-Hillman Reaction, Sai Krishna Kommineni

Theses and Dissertations

Betulin is readily isolated from the bark of birch trees using simple extraction techniques and this molecule as well as its derivatives (eg. betulinic acid) exhibit impressive levels of biological activity. While it is naturally available and shows selective toxicity towards certain cancers, betulin suffers from a general lack of solubility in aqueous conditions. In this regard, we took up a project involving the synthesis of conjugates of betulin with improved solubility characteristics and we were able to identify a series of compounds that showed cytotoxicity against breast and pancreatic cancer cells.

This thesis describes our efforts on the development …

Development Of Functionalized Imidazoles As Potential Therapeutical Agents, Drew Christopher Morgan

Theses and Dissertations

Imidazoles are heterocyclic small molecules that play a major role in medicinal chemistry and drug discovery. There are several drugs in the market which contain imidazoles as the pharmacophore. Metronidazole, an imidazole containing compound, is a prominent antibiotic and antiprotozoal medication used for the treatment of a variety of infections such as amoebiasis, trichomoniasis, bacterial vaginosis, etc. The current work involves the synthesis of small molecule libraries of imidazoles derived from metronidazole using Baylis-Hillman (BH) reaction. BH reaction is a carbon-carbon bond forming reaction and involves the coupling of aldehydes or imines with activated alkenes such as acrylates, acrolein, or …

Functionalized Heterocyclics As Potential Therapeutics, Anupama Indukuri

Theses and Dissertations

Heterocyclic compounds play an important role in pharmaceutical drug development. Several natural products and biologically active compounds contain heterocyclic motifs in them. Multicomponent coupling reactions offer an excellent platform for the synthesis of diverse libraries of heterocyclic compounds. We have been working on the synthesis of novel heterocyclic small molecules utilizing reactions such as Baylis-Hillman reaction, Passerini reaction, Click reaction, reductive amination aldol condensation, etc.

In the current project, we prepared three series of heterocyclic compounds using Passerini and Baylis-Hillman reactions as key steps. Owing to the importance of heterocyclic chemistry in drug discovery and the ease of synthesis, the …

Modification And Characterization Of Chloro-Sugar Derivatives As Anti-Bacterial Agents, Mansi Jani

Theses and Dissertations

Sucralose is an artificial sugar substitute which is most commonly used sweetener among other artificial sweeteners. It is derived from sucrose through a complex chemical process that selectively substitutes three atoms of chlorine for three hydroxyl groups on sucrose molecule, which have shown some inhibition of bacterial growth in gut. The goal of the project was to substitute halide in sucralose in a way that it sustains potential anti-bacterial activity along with sweetening effect, which can be then incorporated into mouthwash formulation. Sucralose is very stable molecule and it also has other physico-chemical advantages which are suitable for our anticipated …

Synthesis Of Novel Library Of Cyanopyrrolidinyl Beta-Amino Alcohols And Matrine Alkaloids, Xiaotian Chen

Theses and Dissertations

Cyanopyrrolidines and beta-Amino alcohols are molecular scaffolds that are highly found in commercially available drugs. We developed a multi-step synthetic method to form a novel library of compounds as inhibitors that share both scaffolds toward potent and selective diabetes therapeutics. Despite the ease for the synthesis of Cyanopyrrolidines, the difficulty of forming high selective beta-Amino alcohols is challenging. We successfully find the best condition for the preference of highly selective mono-alkylation and double-alkylation products and produce them with high yield.

Matrine is an alkaloid found in plants from the genus Sophora and can produce some pharmacological effects such as anti-cancer …