Pharmacy and Pharmaceutical Sciences Commons^™

Probing Binding And Allosteric Mechanisms Of The Kras Interactions With Monobodies And Affimer Proteins : Ensemble-Based Mutational Profiling And Thermodynamic Analysis Of Binding Energetics And Allostery Reveal Diversity Of Functional Hotspots And Cryptic Pockets Linked By Conserved Communication Network, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Guang Hu, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

KRAS, a historically "undruggable" oncogenic driver, has eluded targeted therapies due to its lack of accessible binding pockets in its active state. This study investigates the conformational dynamics, binding mechanisms, and allosteric communication networks of KRAS in complexes with monobodies (12D1, 12D5) and affimer proteins (K6, K3, K69) to characterize the binding and allosteric mechanisms and hotspots of KRAS binding. Through molecular dynamics simulations, mutational scanning, binding free energy analysis and network-based analyses, we identified conserved allosteric hotspots that serve as critical nodes for long-range communication in KRAS. Key residues in β-strand 4 (F78, L80, F82), α-helix 3 (I93, H95, …

Assessment Of H2s-Induced Cracking Susceptibility In Steam Line Pipes And Weld Zones During Geothermal Well Construction, Riene Kaelamanda Pragitta, Yudha Pratesa

Journal of Materials Exploration and Findings

The susceptibility of steam line pipes, especially in the HAZ (heat-affected zone) and weldment areas, to hydrogen sulfide in the geothermal industry is crucial to understand from the early stages, particularly during construction. The combination of tensile stress from residual stresses after welding and metallurgical phase transformation makes the joint areas vulnerable to sulfide stress cracking. This condition becomes even more extreme when the equipment operates during the well stimulation phase. This research assesses the severity of H₂S-induced cracking using NACE MR0175 and ISO 15156-1 standards, focusing on the effects of pH and partial pressure of H₂S (p_{H₂S …}

Mutational Scanning And Binding Free Energy Computations Of The Sars-Cov-2 Spike Complexes With Distinct Groups Of Neutralizing Antibodies: Energetic Drivers Of Convergent Evolution Of Binding Affinity And Immune Escape Hotspots, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Nishank Raisinghani, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The rapid evolution of SARS-CoV-2 has led to the emergence of variants with increased immune evasion capabilities, posing significant challenges to antibody-based therapeutics and vaccines. In this study, we conducted a comprehensive structural and energetic analysis of SARS-CoV-2 spike receptor-binding domain (RBD) complexes with neutralizing antibodies from four distinct groups (A–D), including group A LY-CoV016, group B AZD8895 and REGN10933, group C LY-CoV555, and group D antibodies AZD1061, REGN10987, and LY-CoV1404. Using coarse-grained simplified simulation models, rapid energy-based mutational scanning, and rigorous MM-GBSA binding free energy calculations, we elucidated the molecular mechanisms of antibody binding and escape mechanisms, identified key …

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 …

Amorphous Quininium Aspirinate From Neat Mechanochemistry: Diffracting Nanocrystalline Domains And Quick Recrystallization Upon Exposure To Solvent Vapours, Silvina Pagola, James Howard, Johannes Merkelbach, Danny Stam

Chemistry & Biochemistry Faculty Publications

Quininium aspirinate is mechanochemically prepared as a crystalline solid by liquid-assisted grinding, or as an amorphous phase (as determined by X-ray powder diffraction), by neat grinding or neat ball milling. Our previous work demonstrated using FT-IR spectroscopy that a mechanochemical reaction had occurred in the mechanically treated neat mixtures. Herein is reported that microcrystal electron diffraction (microED) afforded the discovery of two diffracting micron-size particles in the amorphous powder synthesized by manual grinding, among a majority of non-diffracting particles. Remarkably, microED data of one of them led to the known lattice parameters of quininium aspirinate. Furthermore, this so-called 'X-ray amorphous' …

Alpha-Synuclein Interaction With Gedunin, Tony Matundura Nyabayo

Graduate Theses/Dissertations

Parkinson’s disease (PD) and other Proteinopathies develop when α-synuclein misfolds and aggregates into toxic amyloids. While existing treatments for PD are primarily focused on managing its symptoms, a viable solution for slowing down the progress of Parkinson’s disease involves targeting the toxic α-synuclein amyloids. Gedunin, a natural inhibitor of heat shock protein 90, has been extensively used to treat malaria. Also, recent research investigations have shed light on its potential beyond malaria therapy, indicating that Gedunin may offer a possible solution for treating a variety of neurodegenerative diseases. Using plate-based assays, we examined how Gedunin influences α-synuclein fibrillation and its …

Rational Design Of Small Molecules Targeting Mitochondrial Redox Proteins, Matheus Barbosa Belchior

Graduate Theses, Dissertations, and Problem Reports (ETD)

Reactive oxygen species play a crucial role in many cellular processes. Despite being a natural byproduct of cellular metabolism, overexpression of these species causes damage to the cell, leading to cell dysfunction. Central to the regulation of these highly reactive molecule is the mitochondria. Impairment in its function has been associated with oxidative stress within the cell. Herein, a ligand-based and structure-based approach to design new small molecules to inhibit mitochondrial redox proteins associated with oxidative stress and reactive oxygen species. In the first project two molecules were synthesized and characterized as potential monoamine oxidase B inhibitors. Results showed two …

Single-Step Synthesis Of Activated Carbon From Arabica Spent Coffee Ground Using K2co3 As Activator Agent, Ghina Ivana Mieldan, Yuliusman Yuliusman

Journal of Materials Exploration and Findings

Activated carbon is a nanomaterial that is often used as an effective adsorbent. Activated carbon raw materials can use biomass, such as coffee grounds, which can be found along with the growth of public interest in coffee drinks. Chemical activators are used for activation to increase biomass carbon's adsorption capacity. Using K₂CO₃ activator to increase the specific surface area of activated carbon is more harmless than KOH. The use of spent coffee grounds as carbon source and food additive K₂CO₃ as an activator can make food-grade activated carbon that can be used for food. …

Effect Of Alkyd And Polyester Resin Compositions On Corrosion Resistance, Blistering, And Adhesion In Utilization Of Oily Sludge As Anti-Rust Coating Material, Gerets Land Kakalang, Yohanes David Kristianto, Johny Wahyuadi Mudaryoto

Journal of Materials Exploration and Findings

Oil sludge is a waste derived from upstream and downstream activities of the oil and gas industry which is estimated at 10,000 tonnes generated from all PERTAMINA downstream activities spread across various fields, processing units and depots throughout Indonesia. Oil sludge has the same characteristics as asphalt, where asphalt in previous studies can be used as an anti-rust coating, so that the handling of oily sludge can be topped up by reusing and having its own added value. The purpose of this research is to utilise waste oily sludge as an alternative anti-rust coating material and compare alkyd resin 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 …

Computational Logp Calculations And Determination Of Lipophilicity Values Of Fluorinated Morphine Derivatives, Mirabella Romano, Allison Vu, Emily Chen

Student Scholar Symposium Abstracts and Posters

The addictive effect of opioids impacted 60 million people globally in 2023. This opioid crisis necessitates the development of opioid derivatives that maintain analgesic efficacy while minimizing addictive effects from opioid use. The present work focuses on morphine, a commonly prescribed opioid with high affinity to the mu-opioid receptor (MOR). Morphine binds non-selectively within both healthy and inflamed tissue. By modifying morphine’s structure through fluorination to counteract its non-selective binding, the drug’s pharmacological ability to provide effective pain relief comes with a lower risk of addiction. Specifically, the addition of fluorine to differing beta positions of the main binding site …

Synthesis Of Photocleavable Molecules For Neurological Applications, Nishal Madujith Egodawaththa Arachchilage Don

Theses and Dissertations

In recent biomedical research, the precise control of molecular dynamics through light activation has emerged as a powerful tool, particularly in the field of neurobiology. This approach involves the use of photocleavable cages or photoprotective groups (PPGs) that are chemically tethered to biologically active molecules such as neurotransmitters or calcium chelators. These cages remain inert until exposed to specific wavelengths of light, typically in the visible range, triggering the release of the active compound with high spatiotemporal precision.

For neurotransmitter systems, such as glutamate (Glu), which plays a critical role in synaptic transmission and memory formation, researchers have developed novel …

Physicochemical Property Effects On Immune Modulating Polymeric Nanoparticles: Potential Applications In Spinal Cord Injury, Daniel J. Kolpek, Jaechang Kim, Hisham Mohammed, John C. Gensel, Jonghyuck Park

Markey Cancer Center Faculty Publications

Nanoparticles (NPs) offer promising potential as therapeutic agents for inflammation-related diseases, owing to their capabilities in drug delivery and immune modulation. In preclinical studies focusing on spinal cord injury (SCI), polymeric NPs have demonstrated the ability to reprogram innate immune cells. This reprogramming results in redirecting immune cells away from the injury site, downregulating pro-inflammatory signaling, and promoting a regenerative environment post-injury. However, to fully understand the mechanisms driving these effects and maximize therapeutic efficacy, it is crucial to assess NP interactions with innate immune cells. This review examines how the physicochemical properties of polymeric NPs influence their modulation of …

Subterranean Medicinal Bottles Are Treasures That Reveal The Growth Of Lincoln's Early Drug Stores, Mark Griep, June Weber, Erik Schulz, Effie Athanassopoulos

Department of Anthropology: Faculty Publications

Archeologists unearthed medicine bottles embossed with the names of nine early Lincoln (Nebraska) drug stores, giving insight into the rapid growth of pharmacies and health care from the 1880s up to the Pure Food and Drug Act of 1906.

Integrating Data-Driven And Mechanism-Driven Modeling In Drug Discovery And Hepatotoxicity Evaluation, Xuelian Jia

Theses and Dissertations

The pharmacological activities and hepatotoxicity significantly influence the success or failure of new drugs during drug discovery and development. Traditional experimental methods, such as animal models, are costly and time-consuming for chemical testing. There is a great need to develop in vitro and computational modeling to help identify the pharmacological activities and hepatotoxicity potential in the early stage of drug discovery and safety evaluation. In this dissertation, new computational models and associated modeling frameworks were described for predicting the biological profile and hepatotoxicity of chemicals. Firstly, a novel data mining and Quantitative Structure-Activity Relationship (QSAR) workflow was developed to construct …

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 …

Microencapsulation Of Cosmos Caudatus Kunth Extract Using Sodium Alginate And In Vitro Antioxidant Activity Test, Safina Samara Nur Fadlila, Oktavia Eka Puspita, Zubaidah Ningsih, Anna Safitri

Makara Journal of Science

This study aims to encapsulate Cosmos caudatus K. leaf extract in sodium alginate crosslinked with calcium chloride (CaCl₂) as coating materials through freeze-drying. Antioxidant assays were performed to evaluate the applicability of the microcapsules as antidiabetic medicines. Their characteristics, antioxidant activity, and encapsulation efficiency (EE) were also examined. Results indicated that the concentration of sodium alginate and pH influenced the manufacturing process of the microcapsules. The highest EE was obtained at pH 6 and alginate concentration of 2% (w/v). The IC₅₀ for the antioxidant activity of the microcapsules was 139.96 ± 1.094 μg/mL. Scanning electron microscopy confirmed …

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 …

Integrated Computational Approaches: Elucidating Molecular Mechanisms Of Pathogenic Proteins And Designing Novel Inhibitors Against Mycobacterium Tuberculosis And Sars-Cov-2, Justin David Carbone

Theses and Dissertations

Chapter 1 introduces computational strategies in computer aided drug design (CADD), focusing on physics-based methodologies to enhance drug discovery. This chapter also discusses the theoretical foundations and practical applications of molecular dynamics (MD) simulations including free energy and stochastic kinetic analysis. In Chapter 2, CADD methods lead to development of inhibitors targeting the RNA Dependent RNA Polymerase (RdRP) of SARS-CoV-2. Inspired by the nucleotide inhibitor Molnupiravir, we aim to design a combinatorial library of 72 novel inhibitors capable of impeding a dual threat inhibition mechanism inducing lethal mutations along with stalling viral replication with specific selectivity to RdRp over Human …

Electrochemical Modulation Of Surface Plasmon Wave To Investigate Dna-Based Sensing Platforms And Detection Of Sars-Cov2., Anil Sharma

Electronic Theses and Dissertations

This study offers a thorough comparative analysis of optical and electrical signaling strategies for assessing the electrochemical properties of different redox-labeled DNA-based biosensing platforms. In addition, it illustrates the development of an optical interrogation technique with electrochemical modulation of surface plasmon waves (ECM-SPW) as a route for analyzing and implementing DNA-based hybridization sensors. For those quantitative analyses, we chose a model sensing platform composed of a methylene blue (MB)-modified single-stranded DNA (ssDNA) signaling probe and an unlabeled capture ssDNA probe that complements the signaling probe. Two types of signaling probes were employed in this work: one with MB attached to …

Synthesis Of Thermoresponsive Poly(N-Isopropyl Acrylamide) Based Core-Shell And Hollow Shell Nanogel With Tunable Core And Shell Thickness, Mohamad Hijazi, Molla R. Islam

Student Scholar Symposium Abstracts and Posters

Nanogels have emerged as a notably safer and more effective means for drug delivery, primarily due to their adjustable drug-loading capabilities. Hollow-core nanoparticles offer some unique properties that are desirable for drug delivery applications. Initially, silica core nanoparticles were synthesized using the Stöber process at different temperatures where Tetraethoxysilane (TEOS) undergoes hydrolysis in the presence of ethanol and then a condensation reaction to form silica nanoparticles. Scanning Electron Microscopy (SEM) and Optical Microscopy (OM) analysis revealed that the size of silica core particles varied with the synthesis temperature (300 nm at 30°C to 150 at 60°C). The core silica particles …

Apigenin Alleviates Autistic-Like Stereotyped Repetitive Behaviors And Mitigates Brain Oxidative Stress In Mice, Petrilla Jayaprakash, Dmytro Isaev, Keun-Hang Susan Yang, Rami Beiram, Murat Oz, Bassem Sadek

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Studying the involvement of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in neuropsychiatric brain disorders such as autism spectrum disorder (ASD) has gained a growing interest. The flavonoid apigenin (APG) has been confirmed in its pharmacological action as a positive allosteric modulator of α7-nAChRs. However, there is no research describing the pharmacological potential of APG in ASD. The aim of this study was to evaluate the effects of the subchronic systemic treatment of APG (10–30 mg/kg) on ASD-like repetitive and compulsive-like behaviors and oxidative stress status in the hippocampus and cerebellum in BTBR mice, utilizing the reference drug aripiprazole (ARP, 1 …

Methionyl-Trna Synthetase Synthetic And Proofreading Activities Are Determinants Of Antibiotic Persistence, Whitney N. Wood, Miguel Angel Rubio, Lorenzo Eugenio Leiva, Gregory J. Phillips, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Bacterial antibiotic persistence is a phenomenon where bacteria are exposed to an antibiotic and the majority of the population dies while a small subset enters a low metabolic, persistent, state and are able to survive. Once the antibiotic is removed the persistent population can resuscitate and continue growing. Several different molecular mechanisms and pathways have been implicated in this phenomenon. A common mechanism that may underly bacterial antibiotic persistence is perturbations in protein synthesis. To investigate this mechanism, we characterized four distinct metG mutants for their ability to increase antibiotic persistence. Two metG mutants encode changes near the catalytic site …

Mechanistic Investigation Of C—C Bond Activation Of Phosphaalkynes With Pt(0) Complexes, Roberto M. Escobar, Abdurrahman C. Ateşin, Christian Müller, William D. Jones, Tülay Ateşin

Research Symposium

Carbon–carbon (C–C) bond activation has gained increased attention as a direct method for the synthesis of pharmaceuticals. Due to the thermodynamic stability and kinetic inaccessibility of the C–C bonds, however, activation of C–C bonds by homogeneous transition-metal catalysts under mild homogeneous conditions is still a challenge. Most of the systems in which the activation occurs either have aromatization or relief of ring strain as the primary driving force. The activation of unstrained C–C bonds of phosphaalkynes does not have this advantage. This study employs Density Functional Theory (DFT) calculations to elucidate Pt(0)-mediated C–CP bond activation mechanisms in phosphaalkynes. Investigating the …

De Novo Drug Design Using Transformer-Based Machine Translation And Reinforcement Learning Of An Adaptive Monte Carlo Tree Search, Dony Ang, Cyril Rakovski, Hagop S. Atamian

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The discovery of novel therapeutic compounds through de novo drug design represents a critical challenge in the field of pharmaceutical research. Traditional drug discovery approaches are often resource intensive and time consuming, leading researchers to explore innovative methods that harness the power of deep learning and reinforcement learning techniques. Here, we introduce a novel drug design approach called drugAI that leverages the Encoder–Decoder Transformer architecture in tandem with Reinforcement Learning via a Monte Carlo Tree Search (RL-MCTS) to expedite the process of drug discovery while ensuring the production of valid small molecules with drug-like characteristics and strong binding affinities towards …

Advancements In The Synthesis Of Polyoxygenated Oxepanes And Thiepanes For Applications To Natural Products, Aditya R. Pote, Shayne M. Weierbach, Mark W. Peczuh, Kyle M. Lambert

Chemistry & Biochemistry Faculty Publications

Oxepanes are central motifs and tenants of many biologically important molecules, and their synthetic construction often presents a challenge to chemists due to consequential entropic and enthalpic barriers that have limited the synthetic toolbox to access these seven-membered oxacycles. This review covers the breadth of synthetic methods to afford the oxepane/thiepane moiety, with a focus on polyoxygenated oxepanes and includes radical cyclizations, Lewis acid-mediated cyclizations, ring closing-metathesis, Nicholas-Ferrier rearrangement, homologations, and ring-expansion strategies. Implementation of these tactics towards sugar-based and non-sugar based (de novo) approaches is presented alongside their extensive application to the total synthesis of several complex polyoxygenated oxepane-containing …

Design Of Kappa Opioid Receptor Agonists For Potential Treatment Of Multiple Sclerosis, Lindsay Kornberger

Theses and Dissertations--Pharmacy

Multiple Sclerosis (MS) is a neurodegenerative disease of the central nervous system characterized by demyelination and neuroinflammation. There is currently no cure for MS. There is a critically unmet need for the development of pharmacotherapies that can induce remyelination promoting both repair and recovery. The kappa opioid receptor (KOR) has been identified as a potential target for the development of remyelinating pharmacotherapies. KOR activation has been shown to promote functional recovery and remyelination preclinically. However, typical KOR agonists like U50,488 have limitations such as sedation and dysphoria limiting their use. This necessitates further development of new KOR agonists that maintain …

Combined Risk Based Inspection And Fault Tree Analysis For Repetitive 3-Phase Line Piping Leakage At West Java Offshore Topside Facility, Dona Yuliati, Akhmad Herman Yuwono, D. Rizal Asral, Donanta Dhaneswara

Journal of Materials Exploration and Findings

Hydrocarbon releases might result in serious consequences in various aspects. In addition to the contribution to environmental pollution, repetitive leakages need high repair costs. This study aim is to minimize potential repetitive leakage for other typical 3-phase piping systems. We conducted the risk assessment by adopting Risk Based Inspection (RBI) API 581 to identify risk level, calculating piping lifetime, recommended inspection plan and mitigations. The most relevant root causes can be obtained through quantitative Fault Tree Analysis (FTA). Observation and investigation was taken from eight 3-phase piping systems that experienced repetitive leakages. It has been found that the risk level …

Nitrogen Gas Quenching Pressure Effect On Bs S155 Alloy Steel In Vacuum Furnace, Agus Mulyadi Hasanudin, Eddy Sumarno Siradj

Journal of Materials Exploration and Findings

The production of metal and alloy products requires the use of heat treatment, when during the heat treatment process, quenching is a crucial step. The quenching medium can be anything from water, a salt bath, oil, air and gas. In a vacuum furnace, pressurized gas, most frequently nitrogen (N₂) gas, serves as one of the quenching mediums. One of the drawbacks of the quenching process is the distortion and dimensional change of the parts. This paper aims to investigate the influence of nitrogen gas quenching pressure on the distortion and dimensional change of aerospace actuator gear planet parts …

Equine In Vivo Metabolite Profiling Of The Selective Androgen Receptor Modulator Lgd-3303 For Doping Control, Malin Nilsson Broberg, Heather Knych, Ulf Bondesson, Curt Pettersson, Börje Tidstedt, Scott Stanley, Mario Thevis, Mikael Hedeland

UK CARES Faculty Publications

LGD-3303 is a Selective Androgen Receptor Modulator (SARM) that is prohibited in both equine and human sports due to its anabolic properties. The aim of this study was to investigate the equine in vivo metabolite profile of LGD-3303 and identify drug metabolites that can be suitable as new and improved analytical targets for equine doping control. This was performed by an oral administration of 0.05 mg⋅kg 1 LGD-3303 to horses, where blood and urine samples were collected up to 96 h after administration. The in vivo samples consisting of plasma, urine and hydrolyzed urine were analyzed utilizing ultra-high performance liquid …