Medicinal-Pharmaceutical Chemistry Commons^™

Computer Aided Design Of Aromatic Foldamer Targeting Protein-Protein Interaction, Bamidele Towolawi

Graduate Student and Postdoctoral Fellow Symposium

With the computational tools developed in our lab for accurate prediction of structures and solution dynamics of aromatic foldamers, we now target protein-protein interaction (PPI) by appending proteinogenic side chains on the external surfaces of the helical aromatic foldamers. Particularly, the activation of a regulatory protein NF-κB, a key player in the inflammatory response and cell proliferation, involves binding of NEMO (NF-κB Essential Modulator) with linear di-ubiquitin. In this study, we designed various sequences based on established protocols and investigated, by utilizing molecular dynamics (MD) simulations, their potential binding to di-ubiquitin, specifically targeting the NEMO binding interface. This study complements …

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 …

Potential Metabolite Biomarkers Of Multiple Sclerosis From Multiple Biofluids, Fatema Bhinderwala, Heidi E. Roth, Mary Filipi, Samantha Jack, Robert Powers

Robert Powers Publications

Multiple sclerosis (MS) is a chronic and progressive neurological disorder without a cure, but early intervention can slow disease progression and improve the quality of life for MS patients. Obtaining an accurate diagnosis for MS is an arduous and error-prone task that requires a combination of a detailed medical history, a comprehensive neurological exam, clinical tests such as magnetic resonance imaging, and the exclusion of other possible diseases. A simple and definitive biofluid test for MS does not exist but is highly desirable. To address this need, we have employed NMR-based metabolomics to identify potentially unique metabolite biomarkers of MS …

Leveraging The Hmbc To Facilitate Metabolite Identification, Fatema Bhinderwala, Thao Vu, Thomas G. Smith, Julian Kosacki, Darrell D. Marshall, Yuhang Xu, Martha D. Morton, Robert Powers

Department of Chemistry: Faculty Publications

The accuracy and ease of metabolite assignments from a complex mixture are expected to be facilitated by employing a multi-spectral approach. The 2D ¹H-¹³C HSQC and 2D ¹H-¹H-TOCSY are the experiments commonly used for metabolite assignments. The 2D ¹H-¹³C HSQC-TOCSY and 2D ¹H-¹³C HMBC are routinely used by natural products chemists but have seen minimal usage in metabolomics despite the unique information, the nearly complete ¹H-¹H and ¹H-¹³C and spin systems provided by these experiments that may improve the accuracy and reliability …

Novel Inhibitors To Mmpl3 Transporter Of Mycobacterium Tuberculosis By Structure-Based High-Throughput Virtual Screening And Molecular Dynamics Simulations, Hetanshi Choksi, Justin Carbone, Nicholas J. Paradis, Lucas Bennett, Candice Bui-Linh, Chun Wu

College of Science & Mathematics Departmental Research

Tuberculosis (TB)-causing bacterium Mycobacterium tuberculosis (Mtb) utilizes mycolic acids for building the mycobacterial cell wall, which is critical in providing defense against external factors and resisting antibiotic action. MmpL3 is a secondary resistance nodulation division transporter that facilitates the coupled transport of mycolic acid precursor into the periplasm using the proton motive force, thus making it an attractive drug target for TB infection. In 2019, X-ray crystal structures of MmpL3 from M. smegmatis were solved with a promising inhibitor SQ109, which showed promise against drug-resistant TB in Phase II clinical trials. Still, there is a pressing need to discover more …

Cancer-Associated Fibroblast-Derived Acetate Promotes Pancreatic Cancer Development By Altering Polyamine Metabolism Via The Acss2–Sp1–Sat1 Axis, Divya Murthy, Kuldeep S. Attri, Surendra K. Shukla, Ravi Thakur, Nina V. Chaika, Chunbo He, Dezhen Wang, Kanupriya Jha, Aneesha Dasgupta, Ryan J. King, Scott E. Mulder, Joshua Souchek, Teklab Gebregiworgis, Vikant Rai, Rohit Patel, Tuo Hu, Sandeep Rana, Sai Sundeep Kollala, Camila Pacheco, Paul M. Grandgenett, Fang Yu, Vikas Kumar, Audrey J. Lazenby, Adrian R. Black, Susanna Ulhannan, Ajay Jain, Barish H. Edil, David L. Klinkebiel, Robert Powers, Amarnath Natarajan, Michael A. Hollingsworth, Kamiya Mehla2,, Quan Ly, Sarika Chaudhary, Rosa F. Hwang, Kathryn E. Wellen, Pankaj K. Singh

Robert Powers Publications

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP–seq and RNA–seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment …

Development Of Salinomycin Derivatives As Potential Anticancer Agents, Viren Soni

Theses and Dissertations

Salinomycin is a poly-ionophore antibiotic that was originally isolated from Streptomyces albus by Miyazaki and colleagues from Kaken Chemicals Co., Ltd., Tokyo, Japan. Salinomycin exhibits antimicrobial activity against Gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus, Micrococcus flavus, Sarcina lutea, Mycobacterium spp. Some filamentous fungi, Plasmodium falciparum, and Eimeria spp. as well as protozoan parasites responsible for the poultry disease coccidiosis. Hence, it is used in veterinary medicine. In 2009 Gupta et al demonstrated that salinomycin selectively killed human breast cancer stem cells (CSCs) with great efficacy, and the mechanism of action of this novel CSCs molecule was explored. To name …

Tunable Magnetic Coupling In Graphene Nanoribbon Quantum Dots, Peter H. Jacobse, Mamun Sarker, Anshul Saxena, Brookhaven National Laboratory, Ziyi Wang, Emma Berger, Narayana R. Aluru, Alexander Sinitskii, Michael F. Crommie

Department of Chemistry: Faculty Publications

Carbon-based quantum dots (QDs) enable flexible manipulation of electronic behavior at the nanoscale, but controlling their magnetic properties requires atomically precise structural control. While magnetism is observed in organic molecules and graphene nanoribbons (GNRs), GNR precursors enabling bottom-up fabrication of QDs with various spin ground states have not yet been reported. Here the development of a new GNR precursor that results in magnetic QD structures embedded in semiconducting GNRs is reported. Inserting one such molecule into the GNR backbone and graphitizing it results in a QD region hosting one unpaired electron. QDs composed of two precursor molecules exhibit nonmagnetic, antiferromagnetic, …

Purification And Isolation Of Α-Chloro-Β-Lactone Precursor Molecules, Matthew Ellis

ASPIRE 2024

This research investigates the synthesis of α-chloro-β-lactone molecules, focusing on the production, isolation, and purification of two precursor compounds from chloroacetic acid and substituted benzaldehydes. While multiple methods were explored, including EDC, DIC, and DCC catalysis, DCC proved to be most effective in producing higher yields. However, challenges in purification arose due to the formation of byproducts, particularly with DCC, prompting further investigation for efficient extraction and purification techniques. DCC, however, shows a promising route for α-chloro-β-lactone synthesis, despite purification complexities.

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 …

Analyzing Novel Metal Alloys For Glucose Sensing And Electrocatalysis, Anna Grace Boddy

Theses and Dissertations

In pharmaceutical and medicinal chemistry, metals and metal alloys often receive less attention compared to biological or organic compounds due to many factors including toxicity in the body for drug development or the cost of these metals. However, metals can play an important role in pharmaceuticals, having an impact on original cancer drugs, such as platinum used for head and neck tumors. Electrocatalysis is also another topic that receives less attention over topics such as chromatography in pharmaceuticals due to its potential toxic catalysts and voltages that could be harmful to the body. Electrocatalytic sensors can play an important role …

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 …

The Kinetic Modulation Of Α - Synuclein Fibrillation And Toxicity By 4-Phenylbutyric Acid, Kristos Awuah Baffour

Graduate Theses/Dissertations

ABSTRACT

The Protein misfolding and aggregation of alpha-synuclein (α-syn) into neurotoxic amyloids underlies the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). 4-Phenylbutyrate (PBA), an FDA drug approved for treating urea cycle disorders, has garnered significant attention as a potential chemical chaperone for targeting alpha-synuclein (α-syn) aggregation. Using in vitro assays, we demonstrated that PBA treatment alters the pattern of α-syn aggregation, as evidenced by reduced formation of oligomeric species and its increased susceptibility to proteolytic cleavage under the influence of PBA. Proteinase K assay, surface plasmon resonance, and Nile red studies indicate that PBA interacts with the extensive …

A New Approach For Discriminating Spatially Acquired Sers Spectra Using Antiretroviral Drug Emtricitabine As A Test Sample, Jana Hrncirova, Marguerite R. Butler, Meredith R. Clark, Gustavo F. Doncel, John B. Cooper

Chemistry & Biochemistry Faculty Publications

In this study, an antiretroviral drug emtricitabine (also known as FTC or Emtriva) was detected and quantified down to 40 ng/ml by using surface-enhanced Raman spectroscopy (SERS). Its aqueous standards were tested with two types of silver nanoparticles (colloidal and dendritic) using a specially developed aluminum well plate. The SERS spectra were acquired using a Raman scanning device with 30-mu m spatial resolution. The spectral data were analyzed using a new approach for the discrimination of the spatially acquired spectra based on the Quality index (Qi). After the Qi is calculated, the spectral data are sorted based on the Qi. …

Evidence Of Direct Interaction Between Cisplatin And The Caspase-Cleaved Prostate Apoptosis Response-4 Tumor Suppressor, Krishna K. Raut, Samjhana Pandey, Gyanendra Kharel, Steven M. Pascal

Chemistry & Biochemistry Faculty Publications

Prostate apoptosis response-4 (Par-4) tumor suppressor protein has gained attention as a potential therapeutic target owing to its unique ability to selectively induce apoptosis in cancer cells, sensitize them to chemotherapy and radiotherapy, and mitigate drug resistance. It has recently been reported that Par-4 interacts synergistically with cisplatin, a widely used anticancer drug. However, the mechanistic details underlying this relationship remain elusive. In this investigation, we employed an array of biophysical techniques, including circular dichroism spectroscopy, dynamic light scattering, and UV–vis absorption spectroscopy, to characterize the interaction between the active caspase-cleaved Par-4 (cl-Par-4) fragment and cisplatin. Additionally, elemental analysis was …

Synthetic Approaches Of Carbohydrate Based Self-Assembling Systems, Guijun Wang, Anji Chen, Pramod Aryal, Jonathan Bietsch

Chemistry & Biochemistry Faculty Publications

Carbohydrate-based self-assembling systems are essential for the formation of advanced biocompatible materials via a bottom-up approach. The self-assembling of sugar-based small molecules has applications encompassing many research fields and has been studied extensively. In this focused review, we will discuss the synthetic approaches for carbohydrate-based self-assembling (SA) systems, the mechanisms of the assembly, as well as the main properties and applications. This review will mainly cover recent publications in the last four years from January 2020 to December 2023. We will essentially focus on small molecule self-assembly, excluding polymer-based systems, which include various derivatives of monosaccharides, disaccharides, and oligosaccharides. Glycolipids, …

Establishing A Two-Color Fluorescence Probe Assay For The Simultaneous Screening Of Glut5 And Glut2 Fructose Transporters In Live Cells, Oluwanifesimi Mary Afolabi

Dissertations, Master's Theses and Master's Reports

The mammalian facilitative glucose transporter (GLUT) family comprises 14 members that mediate the transport of hexoses across cell membranes. GLUT5 is the only member specific to fructose, and together with GLUT2, which transports fructose in addition to glucose, they make up the primary fructose transporters in humans. This study introduces a novel two-color fluorescence assay designed to simultaneously monitor the activity of GLUT5 and GLUT2 in live cells. 2,5-anhydro-D-mannitol (2,5-AM) a GLUT5 targeting compound has facilitated the development of various fructose-mimicking probes with a wide range of properties, such as radioactive imaging, fluorescent, photoactive, and drug delivery capabilities. Effective and …

Ipq Descriptor

Level 3

No abstract provided.

Balancing Quality Assurance & Innovation In Pharma, Emma Ramnarine

Level 3

At the Pharmaceutical Regulatory Science Team (PRST) workshop on ICH Q9(R1), held at the Technological University Dublin in early June 2023, Boehringer Ingelheim US Biopharma Operations Product Management & Development Operations Head Emma Ramnarine shared her insights on balancing quality assurance and innovation in pharmaceutical manufacturing. She addressed: ● patient-centered transformation ● a watershed moment in her career ● understanding the drug shortage problem ● disruptive collaboration, and ● systems thinking

approaches. Click here for the slides accompanying Ramnarine’s remarks. She connected some of her remarks for the pharmaceutical industry to those made in the previous talk by Ed Hoffman, …

Quality Reborn, Anders Vinther

Level 3

It is time for Quality leaders to not only fulfill the traditional role of ensuring cGMP compliance within the company but also take the Quality profession to the level of business leadership like Deming did in Japan after World War II. FDA has recently stated that they have low confidence in quality management maturity of the pharmaceutical industry.

For quality leaders to also become good business leaders we must educate them in ways that are different from what we currently do. The education should be in the 6 areas

• Visibly Demonstrating Responsibility of Quality
• Risk-Informed Decision Making and Communication
• Engaging …