Medicinal and Pharmaceutical Chemistry Commons^™

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 …

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 …

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 …

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 …

Modified Ysk12-Mend-Sirna In Dendritic Cells For Cancer Immunotherapy, Syed S. Alam

Undergraduate Research Posters

Tumors may induce tolerogenesis through signaling dendritic cells to produce tolerogenic molecules, such as indoleamine 2, 3-dioxygenase 1 (IDO1). Tumor-associated immunosuppression is associated with higher mortality in patients. Small interfering RNA (siRNA) has been shown to silence specific target genes in the target cell. The siRNA associated with these genes could support a gene knockdown of these immunosuppressors and reduce mortality. Delivery of these therapeutic nucleic acids is difficult in vivo because siRNA is easily broken down inside the cell and the bloodstream through present nucleases. Use of liposome polymers has been reviewed extensively in literature. YSK12-C4, a lipid nanoparticle …

Peptidomimetic And Non- Peptidomimetic Derivatives As Possible Sars-Cov-2 Main Protease (Mpro) Inhibitors, Mohammed A. Al Awadh, Mohini S. Ghatge Ph.D, Mona A. Al Khairi, Faik N. Musayev, Akua K. Donkor, Mohammed H. Al Mughram, Abdelsattar M. Omar Ph.D, Moustafa M. El-Araby Ph.D, Martin K. Safo Ph.D

Graduate Research Posters

To design novel inhibitors of the SARS-CoV-2 main protease (Mpro), we investigated the binding mode of the recently reported α-ketoamide inhibitors of this enzyme. Following, we utilized in-silico screening to identify 168 peptidomimetic and non-peptidomimetic compounds that are high probability Mpro binding candidates. The compounds were synthesized in 5 to 10 mg for initial screening for their potential inhibition of Mpro using Fluorescence Resonance Energy Transfer (FRET) assay. The study was conducted using the main protease, MBP-tagged (SARS-CoV-2) Assay Kit (BPS Bioscience, #79955-2), and the fluorescence due to enzymatic cleavage of substrate measured using BMG LABTECH CLARIOstar™, a fluorescent microplate …

Pharmacogenomics And Ssris Appropriateness In Older Community Dwelling African Americans, Wint War Phyo, Lana Sargent, Elvin T. Price

Graduate Research Posters

Background: Depressive and anxiety disorders are among the most common illnesses experienced by older adults (age > 60). The selective serotonin reuptake inhibitors (SSRIs) are preferred class of antidepressants for these disorders due to their high efficacy and safety profiles among older adults. However, SSRIs are metabolized by highly polymorphic cytochrome P450 enzymes, specifically CYP2D6 and CYP2C19. This can lead to variable dose-response outcomes, especially among older African American population.

Objective: Analyze the frequency of CYP2D6 and CYP2C19 polymorphisms in African American older adults who are taking SSRIs and identify potential inappropriate use of SSRIs in these older adults using the …

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 …

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 …

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. …

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 …

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 …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

Glycosaminoglycan Lyases In The Preparation Of Oligosaccharides, Alhumaidi B. Alabbas

Theses and Dissertations

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date.

An alternative approach is to prepare GAG oligosaccharides using …

Rational Design Of Allosteric Modulators Of Hemoglobin As Dual Acting Antisickling Agents, Piyusha P. Pagare

Theses and Dissertations

Intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) remains the principal cause of the pathophysiology associated with sickle cell disease (SCD). Naturally occurring and synthetic allosteric effectors of hemoglobin (AEH) have been investigated as potential therapeutic agents for the treatment of SCD. Several aromatic aldehydes, including vanillin, have been studied previously as AEHs for their antisickling activities. Specifically, these compounds form Schiff- base adduct with Hb to stabilize the oxygenated (R) state, increase Hb affinity for O2 and concomitantly prevent the hypoxia-induced primary pathophysiology of Hb S polymerization and RBC sickling, in turn, ameliorating several of the cascading secondary adverse …

Development Of Small Molecule Neuroprotectants, Ashley Boice

Theses and Dissertations

Neurodegenerative diseases are a class of conditions that lead to progressive atrophy of different parts of the central nervous system (CNS). These diseases lead to devastating clinical outcomes to patients and give rise to an enormous socio-economical burden on society.¹ One commonality among some of the most well-known neurodegenerative disorders, e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), is neuroinflammation.^2-4 Neuroinflammation stems from interactions of the innate immune system with toxins and insults to the central nervous system. In the case of irremovable or chronic insults and toxins, this leads to chronic damaging …

Galantamine's Deconstruction In The Quest Of A Pam Pharmacophore, Malaika Argade

Theses and Dissertations

Alzheimer’s disease is a progressive neurodegenerative disorder generally affecting people above the age of 65 years. Even though the pathophysiological hallmarks of AD were established more than a hundred years ago, there is yet to be a drug that can stop its characteristic neuronal damage. Of the five currently FDA-approved drugs, galantamine has a unique mechanism of action. Apart from being an AChE inhibitor, galantamine can effectively potentiate (positive allosteric modulator) the effect of agonists at nAChRs at concentrations lower than those required for its action as an AChE inhibitor. Perhaps the clinical benefits observed with galantamine are associated mainly …

Elucidation Of Substrate Binding Interactions For Human Organic Cation Transporters 1 (Slc22a1) And 2 (Slc22a2) Using In Silico Homology Modeling In Conjunction With In Vitro Site-Directed Mutagenesis And Kinetic Analysis, Raymond E. Lai

Theses and Dissertations

The organic cation transporters (OCTs) play a critical role in the absorption, distribution and elimination of many drugs, hormones, herbal medicines, and environmental toxins. Given the broad substrate specificity of OCTs, they fall victim to the high susceptibility for contributing to harmful drug-drug interactions. Further defining how human (h)OCTs mechanistically bind to its broad array of substrates will provide significant insight to the understanding and prediction of drug-drug interactions in polypharmacy patients and the advancement of future rational drug design for therapeutics targeting OCTs. The goal of the current study was to elucidate the critical amino acid residues for transporter-substrate …

Chemical Probes For Protein Α-N-Terminal Methylation, Brianna D. Mackie

Theses and Dissertations

While protein α-N-terminal methylation has been known for nearly four decades since it was first uncovered on bacteria ribosomal proteins L33, the function of this modification is still not entirely understood. Recent discoveries have demonstrated α-N-terminal methylation is essential to stabilize the interactions between regulator of chromosome condensation 1 (RCC1) and chromatin during mitosis, to localize and enhance the interaction of centromere proteins (CENPs) with chromatin, and to facilitate the recruitment of DNA damage-binding protein 2 (DDB2) to DNA damage foci. Identification of N-terminal methyltransferase 1 (NTMT1) unveiled the eukaryotic methylation writer for protein α-N-termini. In addition, NTMT2 that shares …

Study Of Molecular Interactions Of Glycosaminoglycans And Glycosaminoglycan Mimetics With Their Protein Targets, Daniel K. Afosah

Theses and Dissertations

Glycosaminoglycans (GAGs) are complex linear chain carbohydrate molecules found on virtually all animal cell surfaces. Owing to their negatively charged nature, GAGs interact with a number of different proteins. Thus, although they have great potential as therapeutic agents, their apparent promiscuous interactions increase their side effect risk. GAG mimetics, including GAG oligosaccharides and non-saccharide GAG mimetics (NSGMs) are viable approaches to address this. This work discusses sulfated benzofuran thrombin inhibitors with submaximal protease inhibition, sulfated diflavonoid inhibitors of plasmin and GAG oligosaccharides with selectivity for human neutrophil elastase (HNE).

Anticoagulants are very important for the treatment of thrombotic diseases. The …

Structure-Activity Relationship Studies Of Bupropion And Related 3-Substituted Methcathinone Analogues At Monoamine Transporters, Abdelrahman R. Shalabi

Theses and Dissertations

The khat plant, catha edulis, has been abused for some time in the Middle East and the African horn for its short-term stimulant effects. However, it was not until 1975 when cathinone, β-ketoamphetamine, was identified as the major stimulant component of khat. Structural analogues of cathinone, synthetic cathinones, are new psychoactive substances available on the clandestine market of numerous countries including the USA. Abuse of these new illicit stimulants is a worldwide growing health concern which necessitates the investigation of the pharmacological properties of these new drugs of abuse. The abuse liabilities of these compounds seem to be related …

Design, Synthesis, And Biological Screening Of Selective Mu Opioid Receptor Ligands As Potential Treatments For Opioid Addiction, Samuel Obeng

Theses and Dissertations

Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling …

Design And Structure-Activity Relationship Of Small Molecule C-Terminal Binding Protein (Ctbp) Inhibitors And Investigation Of The Scope Of Palladium Multi-Walled Carbon Nanotubes (Pd-Mwcnt) Catalyst In C–H Activation Reactions, Sudha Korwar

Theses and Dissertations

C-terminal binding proteins (CtBPs) are transcriptional co-repressors involved in developmental processes, and also implicated in a number of breast, ovarian, colon cancers, and resistance against cancer chemotherapy. CtBP is a validated novel potential anti-cancer target. In this project we sought to develop potent and selective small-molecule inhibitors of CtBP. Using a combination of classical medicinal chemistry and modern computational approaches, we designed a potent inhibitor HIPP (hydroxyimino-3-phenylpropanoic acid) that showed an IC₅₀ of 0.24 μM against recombinant CtBP. Further elucidation of the structure-activity relationship (SAR) of HIPP led to the design of more potent inhibitors 3-Cl HIPP (CtBP IC …

Exploring The Concept Of Human Oct3 Inhibitors As A Novel Class Of Antidepressants, Kavita A. Iyer

Theses and Dissertations

The Dukat laboratory developed 2-amino-6-chloro-3,4-dihydroquinazoline (A6CDQ) as a 5-HT₃ receptor ligand. A6CDQ and one of its positional isomers, the 7-chloro analog A7CDQ, produced antidepressant-like effects in the mouse tail suspension test (TST). We investigated and systematically ruled out a solely 5-HT₃ receptor or hSERT mediated mechanism of antidepressant-like effect for both A6CDQ and A7CDQ.

The role of organic cation transporter 3 (OCT3) as an alternative mechanism in the regulation of neurotransmitters including serotonin (5-HT) and the therapeutic potential of targeting hOCT3 to achieve antidepressant effects has been established. By virtue of possessing protonatable nitrogen atoms, 2-aminodihyroquinazolines could potentially …

Curcumin/Melatonin Hybrids As Neuroprotective Agents For Alzheimer's Disease, John Saathoff

Theses and Dissertations

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting ~5.2 million Americans. Current FDA approved medications provide mainly symptomatic relief and there are no agents available to delay or cure this disease. Multiple factors such as amyloid-β aggregates, dyshomeostasis of biometals, oxidative stress, and neuroinflammation have been implicated in the development of AD. Even though significant advances have been made in understanding the mechanisms leading to AD, the exact etiology still remains elusive. Given AD’s multifactorial nature, a multifunctional strategy of small molecule design would help to identify novel chemical templates. Recently our lab …

Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii

Theses and Dissertations

Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an …

A Simple Method For Discovering Druggable, Specific Glycosaminoglycan-Protein Systems. Elucidation Of Key Principles From Heparin/Heparan Sulfate-Binding Proteins, Aurijit Sarkar, Umesh R. Desai

Psychology Publications

Glycosaminoglycans (GAGs) affect human physiology and pathology by modulating more than 500 proteins. GAG-protein interactions are generally assumed to be ionic and nonspecific, but specific interactions do exist. Here, we present a simple method to identify the GAG-binding site (GBS) on proteins that in turn helps predict high specific GAG–protein systems. Contrary to contemporary thinking, we found that the electrostatic potential at basic arginine and lysine residues neither identifies the GBS consistently, nor its specificity. GBSs are better identified by considering the potential at neutral hydrogen bond donors such as asparagine or glutamine sidechains. Our studies also reveal that an …

Elaboration And Design Of Α7 Nachr Negative Allosteric Modulators, Osama I. Alwassil

Theses and Dissertations

α7 Neuronal nicotinic acetylcholine receptors are one of two major classes of receptors responsible for cholinergic neurotransmission in the central nervous system. The existence of α7 neuronal nAChRs in different regions of the nervous system suggests their involvement in certain essential physiological functions as well as in disorders such as Alzheimer’s disease (AD), drug dependence, and depression. This project was aimed toward the discovery and development of small–molecule arylguanidines that modulate α7 nAChR function with improved subtype-selectivity through an allosteric approach. Identifying the required structural features of these small molecules allowed optimization of their negative allosteric modulator (NAM) actions at …

Psychoactive Synthetic Cathinones (Or 'Bath Salts'): Investigation Of Mechanisms Of Action, Farhana Sakloth

Theses and Dissertations

Synthetic cathinones represent threatening and high abuse-potential designer drugs. These are analogs of cathinone (the b-keto analog of amphetamine (AMPH)) a naturally occurring stimulant found in the plant Catha Edulis. Methcathinone (MCAT) was the first synthetic analog of cathinone to be identified in 1987 by Glennon and co-workers and it exerted its action primarily through the dopamine transporter (DAT). Most central stimulants exert their action via monomaine transporters by causing either the release (e.g. cathinone analogs such as MCAT) or by preventing the reuptake (e.g. cocaine) of the neurotransmitter dopamine (DA) thus increasing the extracellular synaptosomal concentration of this …

Feasibility Of Integrating Tripterygium Wilfordii Into Modern Cancer Therapy For Increased Efficacy And Minimal Toxicity, Ngoc T. Vo

Undergraduate Research Posters

Cancer is the second leading cause of death in the U.S. and millions of novel cancer cases are being diagnosed each year. While chemotherapy and ionizing radiation are effective treatments against these malignant tumors, the adverse effects that accompany such treatments are devastating. In order to find alternative treatment methods with less side effects, we turn to Eastern herbal medicine. Recent scientific research has found that Tripterygium wilfordii, an herbal medicine traditionally used to treat inflammation in China, contains compounds (triptolide and celastrol) that prevent the growth of solid tumors, induce apoptosis, and prevent metastasis of developed tumors. Investigations …