Medicinal-Pharmaceutical Chemistry Commons^™

Supramolecular Assembly In Short Peptide Systems For Selective Metabolite Recognition And Drug Nanoencapsulation, Maithreyi Ramakrishnan

Dissertations, Theses, and Capstone Projects

Short peptides can form adaptive supramolecular assemblies, and understanding how minimal sequences organize around neurometabolites or hydrophobic cancer drugs enables the rational design of functional materials. This thesis combines molecular dynamics with experimental validation to establish design rules linking peptide sequence to emergent structure and function. Chapter 1 outlines the molecular determinants governing peptide assembly. Chapter 2 reviews computational workflows that reveal sequence-dependent conformations and supramolecular organization. Chapter 3 applies these principles to Dynamic Peptide Libraries which identify tetrapeptides that selectively interact with neurometabolites. Chapter 4 extends the same interaction-driven framework to design tryptophan-rich pentapeptides that co-assemble with kinase inhibitors …

Predicting And Decoding Allosteric Binding Sites Using Protein Language Models And Structure-Based Machine Learning: An Energy Landscape-Guided Explainable Ai Framework, Kamila Riedlová, Vít Skrhák, William G. Gatlin, Max Ludwick, Lucas Turano, Marian Novotný, David Hoksza, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Computational prediction of allosteric binding sites in protein structures remains a persistent challenge, as these regulatory pockets evade detection by both sequence-based and structure-based algorithms. Both computational and physical origins of this predictive asymmetry remain insufficiently understood. In this study, we systematically examine the determinants of binding site predictability using a dual framework that integrates a fine-tuned protein language model and the structure-based method P2Rank as complementary tools probing a diverse data set of 453 human kinases, together with a physics-based interpretability layer derived from energy landscape frustration analysis. Both predictors exhibit a sharp and reproducible dichotomy on protein kinases, …

Membrane Organization Of Rheb And Rhoa: Roles In Function And Allosteric Druggability, Chase M. Hutchins

Dissertations and Theses (Open Access)

Small GTPases of the Ras superfamily are membrane-bound molecular switches that regulate nearly all major cellular processes, and their dysregulation drives cancers, neurological disorders, and metabolic diseases. While anchored to cellular membranes, the catalytic domains of small GTPases undergo orientation dynamics, adopting distinct configurations that can occlude or expose effector-binding surfaces and modulate signaling output. These dynamics have been characterized in the Ras oncoproteins, but whether they extend across the superfamily and influence allosteric druggability has remained unknown.

In this dissertation, I address these questions through Rheb and RhoA, two small GTPases with complementary differences in subfamily lineage, membrane localization, …

Exploring The Limitations Of Substrate Scope In Dimethylallyltryptophan Synthases, Evan T. Miller

Theses and Dissertations--Pharmacy

Natural products (NPs), are the largest source of bioactive compounds in Nature, and are essential to the treatment of human disease. Nearly 50% of drugs approved for use from 1981 to 2019 owe some aspect of their development to NPs, either in terms of their structure, pharmacophore, or mechanism of action. However, NPs are difficult to structurally optimize. Chemoenzymatic methods for NP derivatization have been increasingly seen as practical alternatives to traditional synthetic methods. Prenyltransferases (PTs) are involved in the primary and secondary metabolism of plants, bacteria, and fungi, and they are key enzymes in the biosynthesis of many clinically …

Trade-Off Between Limonene & Geraniol-Based Reprocessable And Non-Reprocessable Epoxy Thermosets: Role Of Aliphatic Diamines In Polymer Networks Design, Priyankkumar Kanubhai Patel

Electronic Theses & Dissertations

The growing demand for sustainable materials, driven by environmental concerns and the rapid depletion of fossil fuels, has garnered significant attention in the fabrication of bio-based epoxy thermosets as renewable alternatives to petroleum-derived thermosetting polymers. The present study focuses on the synthesis and characterization of epoxy prepolymer resins derived from limonene and geraniol via a two-step process, followed by the fabrication of thermally cross-linked flexible epoxy thermoset films using various traditional aliphatic diamine curing agents, namely 1,2-ethylenediamine (EDA), 1,4-butylenediamine (BDA), and 1,6-hexamethylenediamine (HDA). Additionally, the incorporation of cystamine, a disulfide-containing diamine, enabled the formation of a covalent adaptable network through …

Antiproliferative Effects Of Salvia On Breast Cancers., Allison C. Portaro

College of Arts & Sciences Senior Theses

Breast cancer is the most common cancer diagnosed in female adults, with 2.3 million new cases worldwide in 2020. Plants have been used in traditional medicine and are a potential source of pharmaceuticals. One example is the large Lamiaceae (mint) family. The Salvia genus, commonly known as the sages, is the largest genus in Lamiaceae with almost 900 known species. Salvia lyrata (lyre-leaved sage) has a history of Native American medicinal use to treat cancers and other ailments resulting in this plant being referred to as ‘cancer weed.’ Extracts were produced from the leaves of S. lyrata, S. lyrata …

Solvation Thermodynamic Mapping Approaches For Computer-Aided Drug Discovery, Vjay Molino

Dissertations, Theses, and Capstone Projects

The drug discovery process is inherently long and costly, prompting the development and integration of computational tools to mitigate these challenges. One of area explored in computer-aided drug discovery is to understand the role of solvation in protein-drug binding and to develop computational tools and methods that can be integrated in the drug discovery process. Grid Inhomogeneous Solvation Theory (GIST) is a tool that provides a framework for mapping solvation thermodynamiproperties of water molecules on the protein surface.This thesis explores the use of GIST in generating pharmacophore models and elucidates the role of solvation in protein structural fluctuations.

One of …

Rwanda's Natural Remedies: A Fresh Look At The Fight Against Malaria, Leandre Nsabimana Ndisanze

Pomona Senior Theses

Malaria remains one of the most devastating parasitic diseases globally, disproportionately affecting sub-Saharan Africa, where Rwanda continues to face high transmission rates and rising resistance to conventional interventions. Despite decades of control efforts, the emergence of drug-resistant Plasmodium falciparum and insecticide-resistant Anopheles mosquitoes threatens to reverse recent gains. This research responds to the urgent need for sustainable and culturally relevant alternatives by exploring the therapeutic potential of Rwandan traditional medicinal plants. These indigenous remedies, long used by local healers, offer an underexplored reservoir of bioactive compounds that may provide the basis for novel antimalarial drugs.

The central hypothesis of this …

Technological Development Of In-Cell Nmr: Microfluidic, Metabolomic, And Fluxomic Approaches, Nicholas Sciolino

Electronic Theses & Dissertations (2024 - present)

In the fields of structural biology, metabolomics, and fluxomics, there is a driving, technique-based concern when it comes to high-resolution spectrometry and its marriage to biological and physiological relevance. Sample preparation often involves cellular perturbation, lysate separation schemes, combinations with non-biological reagents, and timeline slack. Conceptually, the farther we get from the cell, the greater the potential disparity between what exists in vivo and our in vitro manipulations. This is particularly true when seeking to collect data on transfected targets of interest, and on sensitive metabolic equilibria that occur on the order of minutes. The question remains: if we are …

Assessment And Health Benefit Of Vitamin C Using A549 Cell, Yetunde Adepoju

College of Graduate Studies: Theses & Dissertations

Vitamin C (ascorbic acid) is a vital micronutrient recognized for its antioxidant capacity and essential bodily functions, such as collagen formation, neurotransmitter activity, and regulation of the immune system. This study explores how vitamin C can protect and potentially heal cells under oxidative stress and inflammation, using A549 cells, a human lung epithelial cell line, as the model system. The cells were exposed to varying concentrations of vitamin C dissolved in water, DMSO, and 5% DMSO. To assess the outcome, cell viability was measured with an MTT assay. In addition, the expression of key genes related to oxidative stress and …

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 …

Nanoparticles As Antioxidant Agents: A Comprehensive Review, Sulyman Olalekan Ibrahim, Halimat Yusuf Lukman, Fatimat Ronke Abdulkadir, Monsurat Yemisi Bello, Yusuf Oloruntoyin Ayipo, Halimah Funmilayo Babamale, Marili Funmilayo Zubair, Olubunmi Atolani

Al-Bahir

This study seeks to provide a comprehensive overview of the latest progress in the antioxidant properties of nanoparticles. Nanoparticles (NPs) have emerged as a promising tool in several domains of science and industry, including their application as antioxidant agents. The main knowledge gaps seem to be in correctly identifying the make-up of the naturally occurring phytochemicals that give these nano-antioxidants their extraordinary pharmacology and drug-like properties. In many instances, that characterization is done using spectroscopy instrumentation such as fourier-transform Infrared (FT-IR), scanning electron microscope (SEM), and X-ray diffraction analysis (XRD). From literature appraisals, it was discovered that a lot of …

Development Of Platinum(Iv)-Gold(I)-Based Anticancer Agents, Javier E. Lopez-Hernandez

Dissertations, Theses, and Capstone Projects

Heterometallic compounds have emerged as prospective multitarget anticancer drugs. These species may display improved efficacy and physicochemical properties compared to the individual metallic fragments, while helping combat drug resistance by exerting effects on multiple pathways. In this thesis we describe the synthesis of new bi- and tri-metallic compounds based on platinum(IV) compounds containing FDA-approved platinum agents, and gold(I) derivatives with known anticancer properties. We demonstrate their toxicity and selectivity against a small panel of renal, bladder, ovarian, and breast cancer cell lines, as well as their synergistic effects. We have selected a trinuclear PtAu₂compound containing the Pt(IV) core …

Design, Synthesis, And Optimization Of Allosteric Inhibitors Of Hiv-1 Integrase, Krunal H. Patel

Dissertations

The human immunodeficiency virus type 1 (HIV-1) infection remains a global health crisis, necessitating the development of innovative antiviral strategies. During the integration step, HIV-1 integrase (IN) interacts with viral DNA and the cellular cofactor LEDGF/p75 to effectively integrate the reverse transcript into the host chromatin. Recently, a novel class of antiretroviral agents called Allosteric Inhibitors of HIV-1 Integrase (ALLINI) compounds has emerged as a promising avenue in the fight against HIV-1. While originally designed to inhibit IN-LEDGF/p75 interactions, these compounds have been shown to also impact late-stage viral maturation severely through IN multimerization. Induction of IN multimerization interferes with …

An Insight Into The Physicochemical, Drug-Likeness, Pharmacokinetics And Toxicity Profile Of Kigelia Africana (Lam) Bioactive Compounds, Sulyman Olalekan Ibrahim, Halimat Yusuf Lukman, Marili Funmilayo Zubair, Oluwagbemiga Tayo Amusan, Fatimah Ronke Abdulkadri, Bashir Lawal, Lateefat Bello Abdulfatah, Olubunmi Atolani

Al-Bahir

Kigelia africana plant is multipurpose plant whose therapeutic potential has been thoroughly investigated. The physicochemical, solubilities, ADMET, pharmacological, and drug-like properties of this plant have not been reported in details. This study makes use of the information that is currently known on the chemical make-up of the plant to forecast its overall toxicity as well as the potential for the phytochemicals it contains to be employed in medication discovery. The study also employed free web servers for the lipophilicity, water solubility, drug-likness, bioavailability score, medicinal chemistry and toxicological profiling of the compounds of K. africana. Artemether, a known antimalaria …

Investigating The Activity Of Alternative Warheads For Targeted Covalent Inhibition Of The Inhibitor Vertebrate Lysozyme Protein From Pseudomonas Aeruginosa, Katie Hambrick

Master of Science in Chemical Sciences Theses

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative bacterium that causes blood and lung infections in hospital environments due to its ability to survive on improperly sterilized medical equipment. P. aeruginosa has developed several multi-drug resistance mechanisms that make it very difficult to treat with current antibiotics.¹ This presents the need for a new class of antibiotics that cannot be overcome by P. aeruginosa’s mechanisms of resistance.

The primary goal of this project was to develop a small library of inhibitors that could later be incorporated into lead compounds for novel antibiotic drug discovery. One of P. …

Synthesis And Study Of High-Spin Stable Organic Radicals For Electrical Conductors And Mannosamine Nitroxide For Mri Contrast Agents, Shuyang Zhang

Department of Chemistry: Dissertations, Theses, and Student Research

In the first project, we describe the synthesis of an ambient stable high spin organic diradical 4 based on the Blatter moiety. The high-spin (S = 1) organic diradical 4, which consists of two Blatter radical moieties in a conjugated structure, exhibits a nearly exclusive population (88%) on triplet ground state at room temperature as a consequence of a large single-triplet energy gap (ΔEST = 0.5 kcal/mol). The target diradical molecule is synthesized over five steps with structural confirmation by single-crystal X-ray diffraction. The thermogravimetric analysis (TGA) shows the onset of decomposition at ~264 oC, indicating the diradical molecule has …

The Development Of Novel Radioimmunoconjugates For The Pet Imaging And Radioimmunotherapy Of Cancer, Samantha M. Sarrett

Dissertations, Theses, and Capstone Projects

Antibodies have long played a vital role in nuclear medicine for both the diagnosis and therapy of various malignancies. The role and development of antibodies in nuclear medicine can be broadly separated into three different categories: 1) bioconjugation strategies, 2) immunoPET imaging, and 3) radioimmunotherapy. This dissertation will attempt to comprehensively cover each of these categories through a series of studies, protocols, and reviews. For the bioconjugation strategies, we will describe the development of a novel site-selective bioconjugation strategy using an innovative lysine-targeting reagent, PFP-bisN₃, to prepare [⁸⁹Zr]Zr-^SSKDFO-pertuzumab for visualizing HER2+ breast cancer. Further, …

Development And Biological Evaluation Of Selective Small-Molecule Inhibitors Of The Human Cytochrome P450 1b1, Austin Hachey

Theses and Dissertations--Chemistry

The human cytochrome P450 1B1 (CYP1B1) is an emerging target for small- molecule therapeutics. Several solid tumors overexpress CYP1B1 to the degree that it has been referred to as a universal tumor antigen. Conversely, its expression is low in healthy tissues. CYP1B1 may drive tumorigenesis through promoting the formation of reactive toxins from environmental pollutants or from endogenous hormone substrates. Additionally, the expression of CYP1B1 in tumors is associated with resistance to several common chemotherapies and with poor prognoses in cancer patients. However, inhibiting CYP1B1 with small molecules has been demonstrated in cellular and murine model systems to reverse this …

Development Of A Chemical Biology Approach To Uncover The Influence Of Sequence Variations On Ces1 Activity In Live Cells, Samuel James Knebel

Masters Theses

Drug metabolism is the biochemical process of modifying drugs to detoxify and remove them through enzymatic transformations. These biotransformation’s occur primarily in the liver and are critical to understanding how pharmaceutical compounds are chemically altered inside the human body. Human carboxylesterases (CESs) catalyze the hydrolysis of esters, amides, thioesters, and carbamates. CES-mediated hydrolysis plays an important role in the metabolism of many drugs including the first FDA approved antiviral treatment for COVID-19, remdesivir (Veklury), the seizure control medication rufinamide (Banzel), and the flu antiviral drug oseltamivir (Tamiflu). CES activity is known to be influenced by a variety of factors including …

Designing And Synthesizing A Warhead-Fragment Inhibitory Ligand For Ivyp1 Through Fragment-Based Drug Discovery, Samuel Moore

Symposium of Student Scholars

Fragment-based drug discovery (FBDD) is a powerful tool for developing anticancer and antimicrobial agents. Within this, magnetic resonance spectroscopy (NMR) provides a comprehensive qualitative and quantitative approach to screening and validating weak and robust binders with targeted proteins, making NMR among the most attractive strategies in FBDD. Inhibitor of vertebrate lysozyme (Ivyp1) of P. aeruginosa serves as an excellent target because of its active cellular location and implications in clinical prognosis for cystic fibrosis and immunocompromised patients. This study uses current NMR and biophysical techniques to develop a covalent, fragment-linked warhead inhibitor for Ivyp1 through synthetic methods, warhead linking, and …

Targeting Platelets Using Ionic Liquid Coated Nanoparticles, Karen Mun Wong

Honors Theses

Platelets are key players in our body’s inflammatory processes upon activation, which can create physiological problems. Researchers are actively seeking solutions by targeting platelets with therapeutics. The objective of the research in this thesis was to investigate a new and potentially less invasive drug delivery platform using nanoparticles. The topic of the project was to explore the world of ionic liquids and their abilities, when coated on nanoparticles, to bind to platelets. A library of choline carboxylic acid-based ionic liquids (ILs) was first synthesized via salt metathesis while PLGA-based nanoparticles were simultaneously being synthesized via the nanoprecipitation method. The ionic …

Fast Photochemical Oxidation And Footprinting Of Proteins Via Trifluoromethyl Radical Chemistry, Elaine Morrow

Honors Theses

Fast photochemical oxidation of proteins (FPOP) is a useful tool in proteomics because of the ability for modifications to occur on the scale of microseconds which reduces the modifications to tertiary and quaternary structure allowing for more accurate labeling of the protein. Labels for FPOP are generated from various radicals in our experiments which include hydroxyl radicals and trifluoromethyl radicals. Hydroxyl radicals are easily generated by using an excimer laser (KrF laser, 248 nm) or a UV flash lamp (as a part of the Fox™ System) by the photolysis of hydrogen peroxide. Trifluoromethyl radicals, however, need hydroxyl radicals to be …

Synthesis And Characterization Of A Novel Reaction-Based Azaborine Fluorescent Probe Capable Of Selectively Detect Carbon Monoxide Based On Palladium-Mediated Carbonylation Chemistry, Samuel Moore, Carl Jacky Saint-Louis

Symposium of Student Scholars

Azaborines are fascinating compounds because they possess valuable properties such as photochemical stability, have high molar absorption coefficient and high fluorescent quantum yields, as well as large Stokes shifts and tunable absorption/emission spectra. Here, we designed, synthesized, and will examine a novel reaction-based azaborine fluorescent probe capable of selectively detect carbon monoxide (CO) based on palladium-mediated carbonylation chemistry. This novel azaborine fluorescent probe will exhibit high selectivity for CO and display a robust turn-on fluorescent response in the presence of CO in aqueous buffer solution.

1st Place Contest Entry: Designing Hollow Nanogels For Drug Delivery Applications, Mo Hijazi

Kevin and Tam Ross Undergraduate Research Prize

This is Mo Hijazi's submission for the 2022 Kevin and Tam Ross Undergraduate Research Prize, which won first place. It contains their essay on using library resources, their bibliography, and a summary of their research project on hollow-core nanogels.

Mo is a second-year student at Chapman University, majoring in Biological Sciences. Their faculty mentor is Dr. Molla Islam.

The Development Of Inhibitors For Sars-Cov-2 Orf8, My Thanh Thao Nguyen

CSB and SJU Distinguished Thesis

An unexpected outbreak of SARS-CoV-2 caused a worldwide pandemic in 2020. Many repurposed drugs were tested, but there are currently only three FDA approved antivirals (Merck’s antiviral Molnupiravir, Pfizer’s antiviral Paxlovid, and Remdisivir).1 Most of the antiviral drugs tested SARS-CoV-2 main protease and RNA-dependent RNA polymerase. However, it is important to explore different drug targets of SARS-CoV-2 to prepare for the virus mutations of the future. This research looks at an alternative approach in which SARSCoV- 2 Open Reading Frame 8 (ORF8), which has been shown to be a rapidly evolving hypervariable gene, was chosen to be the protein of …

Sars-Cov-2 Main Protease Inhibitors Repurposed For Hiv-1 Protease Binding, Jacob Minkkinen

CSB and SJU Distinguished Thesis

Severe acute respiratory syndrome (SARS-CoV-2) led to the COVID-19 global pandemic, with over 460 million cases of infection and over 6 million deaths since the start of the pandemic. SARS-CoV-2 is a retrovirus that utilizes a main protease (Mpro). Mpro is a catalytic cys/his protease. Several treatments were proposed to stop the pandemic including repurposing drugs to inhibit the Mpro. Another retrovirus that uses a protease is human immunodeficiency virus (HIV-1) which has been a global epidemic for 40 years and is a devastating disease that attacks the immune system. HIV-1 has infected 79.5 million people and has killed an …

Structural And Computational Studies Of The Sars-Cov-2 Spike Protein Binding Mechanisms With Nanobodies: From Structure And Dynamics To Avidity-Driven Nanobody Engineering, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Nanobodies provide important advantages over traditional antibodies, including their smaller size and robust biochemical properties such as high thermal stability, high solubility, and the ability to be bioengineered into novel multivalent, multi-specific, and high-affinity molecules, making them a class of emerging powerful therapies against SARS-CoV-2. Recent research efforts on the design, protein engineering, and structure-functional characterization of nanobodies and their binding with SARS-CoV-2 S proteins reflected a growing realization that nanobody combinations can exploit distinct binding epitopes and leverage the intrinsic plasticity of the conformational landscape for the SARS-CoV-2 S protein to produce efficient neutralizing and mutation resistant characteristics. Structural …

Allosteric Determinants Of The Sars-Cov-2 Spike Protein Binding With Nanobodies: Examining Mechanisms Of Mutational Escape And Sensitivity Of The Omicron Variant, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric …

Ppld Is A De-N-Acetylase Of The Cell Wall Linkage Unit Of Streptococcal Rhamnopolysaccharides, Jeffrey S. Rush, Prakash Parajuli, Alessandro Ruda, Jian Li, Amol Arunrao Pohane, Svetlana Zamakhaeva, Mohammad M. Rahman, Jennifer C. Chang, Artemis Gogos, Cameron W. Kenner, Gérard Lambeau, Michael J. Federle, Konstantin V. Korotkov, Göran Widmalm, Natalia Korotkova

Molecular and Cellular Biochemistry Faculty Publications

The cell wall of the human bacterial pathogen Group A Streptococcus (GAS) consists of peptidoglycan decorated with the Lancefield group A carbohydrate (GAC). GAC is a promising target for the development of GAS vaccines. In this study, employing chemical, compositional, and NMR methods, we show that GAC is attached to peptidoglycan via glucosamine 1-phosphate. This structural feature makes the GAC-peptidoglycan linkage highly sensitive to cleavage by nitrous acid and resistant to mild acid conditions. Using this characteristic of the GAS cell wall, we identify PplD as a protein required for deacetylation of linkage N-acetylglucosamine (GlcNAc). X-ray structural analysis indicates …