Pharmaceutics and Drug Design Commons^™

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 …

Incorporating Solvation Thermodynamic Mapping In Computer-Aided Drug Design, Yeonji Ji

Dissertations, Theses, and Capstone Projects

Advancements in computational techniques have revolutionized structure-based drug design, substantially improving the efficiency and effectiveness of the drug discovery process by reducing time, costs, and labor requirements. These advancements include various methods, such as investigating small molecule ligands binding to proteins, exploring alternative protein conformations, and solvation mapping on the protein surfaces. Among these methods, understanding the correlation between protein-ligand binding and the role of solvation is important.

A fundamental concept in protein-ligand binding is shape and electrostatic complementarity, which is complicated by the inherent flexibility of proteins. In the absence of small molecule ligands, proteins are complementary to surface …

Targeting Strategies To Optimize The Therapeutic Potential Of Gold Compounds Against Her2-Positive Breast Cancers, Afruja Ahad

Dissertations, Theses, and Capstone Projects

The overexpression of HER2 accounts for 20-30% of breast cancer tumors and not only serves as a marker for poor predictive clinical outcomes but also as a target for treatment. Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutic drugs to provide targeted treatment without toxicity to normal tissue. Most of the ADCs currently in the clinic for cancer chemotherapy are based on complex organic molecules. In contrast, the conjugation of metallodrugs to mAbs has been overlooked when there is enormous potential in this area with the resurgence of metal-based drugs as prospective cancer …

Nanoparticles For Applications In Specific Diagnostics And Precision Medicine, Naxhije Berisha

Dissertations, Theses, and Capstone Projects

Heterogeneity is common in the expression of cancer and treatment response. Precision medicine enables healthcare providers to tailor medical care to an individual's distinct genetic and environmental makeup. This customization has the potential to result in more efficient treatments while minimizing side effects. We believe that by studying the interface of nanotechnology and cancer medicine we can elucidate innovative solutions that address the challenges of disease heterogeneity. This includes advancements in drug delivery, formulations development, and diagnostic sensing. We highlight three studies that use nanotechnology for applications in precision medicine. In Chapter 2, we highlight design optimization of drug formulations …

Effectiveness And Safety Of Apixaban Vs Warfarin In Patients With Venous Thromboembolism With Risk Factors For Bleeding Or For Recurrences, Alexander T. Cohen, Janvi Sah, Amol D. Dhamane, Dionne M. Hines, Theodore Lee, Lisa Rosenblatt, Birol Emir, Allison Keshishian, Huseyin Yuce, Xuemei Luo

Publications and Research

Introduction

Patients at increased risk of bleeding and recurrent VTE who develop venous thromboembolism (VTE) present challenges for clinical management. This study evaluated the effectiveness and safety of apixaban vs warfarin in patients with VTE who have risk factors for bleeding or recurrences.

Methods

Adult patients with VTE initiating apixaban or warfarin were identified from five claims databases. Stabilized inverse probability treatment weighting (IPTW) was used to balance characteristics between cohorts for the main analysis. Subgroup interaction analyses were conducted to evaluate treatment effects among patients with and without each of the conditions that increased the risk of bleeding (thrombocytopenia …

Effectiveness And Safety Of Apixaban Vs Warfarin Among Venous Thromboembolism Patients At High-Risk Of Bleeding, Alexander T. Cohen, Janvi Sah, A. D. Dhamane, Theodore Lee, Lisa Rosenblatt, Patrick Hlavacek, Birol Emir, Allison V. Keshishian, Huseyin Yuce, Xuemei Luo

Publications and Research

This study evaluated effectiveness and safety of apixaban versus warfarin among venous thromboembolism patients at high-risk of bleeding (defined as having at least one of the following bleeding risk factors: ≥75 years; used antiplatelet, NSAIDs, or corticosteroids; had prior gastrointestinal bleeding or gastrointestinal-related conditions; late stage chronic kidney disease). Adult venous thromboembolism patients initiating apixaban or warfarin with ≥1 bleeding risk factor were identified from Medicare and four commercial claims databases in the United States. To balance characteristics between apixaban and warfarin patients, stabilized inverse probability treatment weighting was conducted. Cox proportional hazards models were used to estimate the risk …

An Evaluation Of The Effect Of The Oxycontin® Reformulation On Unintentional Fatal And Non-Fatal Overdose, Daniel C. Beachler, Kelsey Hall, Renu Garg, Geetanjoli Banerjee, Ling Li, Luke Boulanger, Huseyin Yuce, Alexander M. Walker

Publications and Research

Objectives: OxyContin® was reformulated with a polyethylene oxide matrix in August 2010 to reduce the potential for intravenous abuse and for abuse by insufflation. The objective of this study was to evaluate the impact of OxyContin’s reformulation on overdose risk for individuals dispensed OxyContin in comparison to those dispensed other opioids under regular care. Methods: Three national insurance databases with National Death Index linkage identified OD in individuals with any dispensing of OxyContin or a primary comparator opioid (ER morphine, transdermal fentanyl, or methadone) between July 2008 through September 2015. A difference-in-differences design was used to compare the pre-post reformulation …

A Role For Retinoids In The Treatment Of Covid-19?, Steven E. Trasino

Publications and Research

The 2020 global outbreak of the novel coronavirus (SARS-CoV-2 or COVID-19) is a serious threat to international health, and thus, there is an urgent need for discoverynof novel therapies or use of repurposed drugs that can make a significant impact on slowing the spread of the virus. Type 1 interferons (IFN-I) are a family cytokines of the early innate immune response to viruses that are being tested against SARSCoV- 2. However, coronaviruses similar to SARS-CoV-2 can suppress host IFN-I antiviral responses. Retinoids are a family molecules related to vitamin A that possess robust immune-modulating properties, including the ability to increase …

Exploration Of The Inhibitory Properties Of The Nucleoside Antibiotic Salicyl-Ams And Analogues Targeting Siderophore Biosynthesis In Mycobacterium Tuberculosis, Glennon Bythrow

Dissertations, Theses, and Capstone Projects

Mycobacterium tuberculosis (Mtb) is a resilient, obligate bacterial pathogen responsible for pulmonary tuberculosis disease (TB), that has upheld a significant impact on global public health throughout history. The World Health Organization (WHO) approximates nearly 10 million new TB cases arose in 2017 alone, accounting for 1.6 million deaths. There has been a notable rise in TB cases produced by multidrug‑resistant (MDR) and extensively drug-resistant (XDR) strains of Mtb. This, along with the intrinsic resistance of Mtb to many standard drugs and poor patient compliance, is deeply impacting global control of TB. Among the several strategies currently in …

Comparative Characteristics Of Antibacterial Activity Of Plants Growing In The Central Part Of The Republic Of Tajikistan., Saidbeg Satorov, F. Mirzoeva, Sh. Satorov, M. Vakhidova, Vyacheslav Dushenkov

Publications and Research

Objective: To evaluate the spectrum of antibacterial activity of plants growing in the central part of the Republic of Tajikistan.
Methods: The antibacterial properties of 18 plant species from the 14 families were studied. The extract samples on dry filter discs were prepared according to the method developed at Rutgers University. Screens-to-Nature (STN) and disc diffusion (DD) methods were used to assess antimicrobial properties of the extracts. The antimicrobial activity of plant extracts was determined against four types of pathogenic standard museum strains of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, as well as …

Structure-Activity Profiling Of Alkaloid Natural Product Pharmacophores Against A Schistosoma Serotonin Receptor, Jonathan S. Marchant, Wayne W. Harding, John D. Chan

Publications and Research

Serotonin (5-HT) is an important regulator of numerous aspects of flatworm biology, ranging from neuromuscularfunctionto sexualmaturationandegglaying. Intheparasiticblood flukeSchistosomamansoni,5-HTtargets several G-protein coupled receptors (GPCRs), one of which has been demonstrated to couple to cAMP and regulate parasite movement. This receptor, Sm.5HTRL, has been successfully co-expressed in mammalian cells alongside a luminescent cAMP-biosensor, enabling pharmacological profiling for candidate anti-schistosomal drugs. Here, we have utilized this assay to perform structure-activity investigations of 143 compounds containing previously identified alkaloid natural product pharmacophores (tryptamines, aporphines and protoberberines) shown to regulate Sm.5HTRL. These experiments mapped regions of the tryptamine pharmacophore amenable and intolerant to substitution, highlighting …