Medicinal-Pharmaceutical Chemistry Commons^™

Integrating Conformational Dynamics And Perturbation-Based Network Modeling For Mutational Profiling Of Binding And Allostery In The Sars-Cov-2 Spike Variant Complexes With Antibodies: Balancing Local And Global Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

n this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-CoV-2 spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify the local and global effects of mutations in the complexes, identify protein stability centers, characterize binding energy hotspots, and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific signatures of protein stability and flexibility of the …

Multiplexed Monitoring Of Neurochemicals Via Electrografting- Enabled Site-Selective Functionalization Of Aptamers On Field-Effect Transistors, Zan Gao, Guangfu Wu, Yang Song, Huijie Li, Yuxuan Zhang, Michael J. Schneider, Yingqi Qiang, Jackson Kaszas, Zhengyan Weng, He Sun, Bryan D. Huey, Rebecca Lai, Yi Zhang

Department of Chemistry: Faculty Publications

Neurochemical corelease has received much attention in understanding brain activity and cognition. Despite many attempts, the multiplexed monitoring of coreleased neurochemicals with spatiotemporal precision and minimal crosstalk using existing methods remains challenging. Here, we report a soft neural probe for multiplexed neurochemical monitoring via the electrografting-assisted site-selective functionalization of aptamers on graphene field-effect transistors (G-FETs). The neural probes possess excellent flexibility, ultralight mass (28 mg), and a nearly cellular-scale dimension of 50 μm × 50 μm for each G-FET. As a demonstration, we show that G-FETs with electrochemically grafted molecular linkers (−COOH or −NH2) and specific aptamers can be used …

Co-Microencapsulation Of Ruellia Tuberosa L. And Cosmos Caudatus K. Extracts For Pharmaceutical Applications, Choirin Annisa, Sasangka Prasetyawan, Anna Safitri

Makara Journal of Science

This study aims to co-microencapsulate the Ruellia tuberosa L. and Cosmos caudatus K. extracts, with chitosan–sodium tripolyphosphate (Na-TPP) as coating material. α-Amylase inhibition and antioxidant assays were conducted to determine the potential of microcapsules used as antidiabetic agents. The microcapsules were manufactured under the influences of pH, Na-TPP concentration, and stirring time. The optimum microencapsulation conditions were selected based on the highest encapsulation efficiency. The optimum microencapsulation conditions were a pH of 4, Na-TPP concentration of 0.15% (w/v), and stirring time of 60 min. The microcapsules exhibited an IC₅₀ (inhibitory concentration) value of 223.64 ± 0.81 µg/mL and an …

Asymmetrical Spectral Continuum Between Anti-Stokes And Stokes Scattering Revealed In Low-Frequency Surface-Enhanced Raman Spectroscopy, Shuo Sun, Dhanusha T.N. Rathnayake, Yinsheng Guo

Department of Chemistry: Faculty Publications

An asymmetrical spectral continuum is observed in low-frequency surface-enhanced Raman spectroscopy (LF-SERS) in the terahertz (THz) region. This background continuum appears as a flat baseline in the Stokes side and a slope in the anti-Stokes side. Analysis shows this asymmetry originates from the different scaling of anti-Stokes and Stokes scattering with respect to the Bose−Einstein distribution. Such asymmetry is readily visible, under room temperature, in the low-frequency THz spectral range. Accounting for this spectral intensity asymmetry reveals the intrinsic continuum background of electronic origin, differing from local normal modes and collective relaxational motions. We also describe a numerical method, independent …

Stereocontrolled Access To Δ-Lactone-Fused-Γ-Lactams Bearing Angular Benzylic Quaternary Stereocenters, Timothy K. Beng, Morgan J. Rodriguez, Claire Borg

All Faculty Scholarship for the College of the Sciences

C-fused γ-lactam-lactones are resident in several bioactive molecules, including anticancer agents such as omuralide. In this embodiment, we report mild conditions for the catalytic halolactonization of lactam-tethered 5-aryl-4(E)-pentenoic acids. The use of dichloromethane as the solvent and Ph₃PS as the catalyst led to predominant 6-endo-trig cyclization and furnished the trans-fused-γ-lactam-δ-lactones. The transformation is modular, regioselective, chemoselective, and diastereoselective. The γ-lactam-δ-lactones bear angular quaternary benzylic stereocenters, which is noteworthy since the presence of a quaternary carbon in bioactive small molecules often promotes an element of conformational restriction that imparts potency, selectivity, and metabolic stability. The …

Noncanonical Amino Acid Mutagenesis In Response To Recoding Signal-Enhanced Quadruplet Codons, Yan Chen, Xinyuan He, University Of Nebraska-Lincoln, Kun Liu, Tian Gao, Wei Niu, Jiantao Guo

Department of Chemistry: Faculty Publications

While amber suppression is the most common approach to introduce noncanonical amino acids into proteins in live cells, quadruplet codon decoding has potential to enable a greatly expanded genetic code with up to 256 new codons for protein biosynthesis. Since triplet codons are the predominant form of genetic code in nature, quadruplet codon decoding often displays limited efficiency. In this work, we exploited a new approach to significantly improve quadruplet UAGN and AGGN (N = A, U, G, C) codon decoding efficiency by using recoding signals imbedded in mRNA. With representative recoding signals, the expression level of mutant proteins containing …

Advanced Cnc/Peg/Pdmaa Semi-Ipn Hydrogel For Drug Delivery Management In Wound Healing, Samia Afrin, Md. Shahruzzaman, Papia Haque, Md. Sazedul Islam, Shafiul Hossain, Taslim Ur Rashid, Tanvir Ahmed, Makoto Takafuji, Mohammed Mizanur Rahman

Department of Chemistry: Faculty Publications

A Semi Interpenetrating Polymer Network (semi-IPN) hydrogel was prepared and loaded with an antibiotic drug, gentamicin, to investigate the wound healing activity of this system. The semi-IPN hydrogel was synthesized by combining natural polymer cellulose nanocrystal (CNC) and synthetic polymer polyethylene glycol (PEG) and poly (N,N0-dimethyl acrylamide) (PDMAA), which was initially added as a monomer dimethyl acrylamide (DMAA). CNC was prepared from locally obtained jute fibers, dispersed in a PEG-NaOH solvent systemand then mixed with monomer DMAA, where polymerization was initiated by an initiator potassium persulphate (KPS) and cross-linked by N,N0-methylenebisacrylamide (NMBA). The size, morphology, biocompatibility, antimicrobial activity, thermal and …

Synthesis, Characterization, And Bioactivity Of 3-Substituted Coumarins As An Undergraduate Project, Karsen King, Nicholas Campbell, Ronald Okoth, Wathsala Medawala

Georgia Journal of Science

Coumarins are an important class of phytochemicals, a chemical defense presumed to be secreted by plants. More recently, Coumarins have gathered popularity for their basis in anti-cancer agents. This paper dives into the organic synthesis of two 3-substituted coumarins from o-vanillin using the Knoevenagel condensation reaction. The 3-substituted coumarin were characterized using melting point analysis, ¹H-NMR, and UV-Vis spectroscopy. In addition, the anticancer activity of synthesized 3-substituted coumarin compounds were assayed against topoisomeraseIIα, which is the target enzyme of FDA approved anti-cancer drug etoposide since it is an active enzyme in cancer cell replication. The demonstrated procedures can be …

Biophysical Insight Into The Sars-Cov2 Spike–Ace2 Interaction And Its Modulation By Hepcidin Through A Multifaceted Computational Approach, Hamid Hadi-Alijanvand, Luisa Di Paola, Guang Hu, David M. Leitner, Gennady M. Verkhivker, Peixin Sun, Humanath Poudel, Alessandro Giuliani

Mathematics, Physics, and Computer Science Faculty Articles and Research

At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection …

Synthetic Investigations In Chemical Probe Development Part 1: Design And Synthesis Of Novel Triton X-405 Adenosine Conjugates; Part 2: Synthesis Of 2,8-Dihydroxychrysene, Rachel Irene Hammond

Honors Theses

Although not drugs themselves, chemical probes are a necessary tool in biomedical research for the interrogation of biological systems. In the present synthetic investigation, two chemical probes were developed – a Triton X-405 adenosine conjugate (TX-405A) and 2,8-dihydroxychrysene. The designed TX-405A conjugate was generated in four steps through tosylation and amination of TX-405 such that EDC-coupling of TX-amine with 2’,3’-Isopropylidene adenosine-5’-carboxylic acid afforded TX-405A following acetonide deprotection. The development of TX-405A represents the first report of the synthesis and utilization of a detergent-linked dosimeter. The synthesis of 2,8-dihydroxychrysene provided an in-depth exploration on the unique reactivity of chrysene. The desired …

The Design Of A Pcr-Based Assay To Detect And Isolate The Serine Palmitolytransferase Gene From Environmental Bacteria, Lana Taylor

Honors Theses

Sphingolipids are a natural class of lipids that function as structural elements of cell membranes and signaling molecules for important cellular activities such as cell growth, differentiation, apoptosis, recognition, and adhesion. These lipids can be found universally in eukaryotic cells as well as some species of bacteria, such as those found in the human gut microbiome and in the environment in soils. Though sphingolipid production is rare in bacteria, both eukaryotic and prokaryotic sphingolipid biosynthesis begin with the condensation of serine and palmitoyl CoA into 3-ketodihydrosphingosine catalyzed by the enzyme serine palmitoyltransferase (SPT). In recent years, several studies have shown …

Drug Loaded Mesoporous Nanocarriers For The Detection Of Aspergillosis, Madeline Jewel Brooks

Honors Capstone Projects and Theses

No abstract provided.

Extraction And Partial Purification Of An Antibiotic-Like Compound From The Soil Bacterium Rhodococcus Strain Kchxc3, Elizabeth Bond

Undergraduate Honors Theses

Rhodococcus bacteria have many secondary metabolic pathways that may produce novel natural products. The bacterium Rhodococcus strain KCHXC3 was isolated from a soil sample collected near Kingsport, Tennessee and was found to produce an inhibitory compound active against a broad array of bacterial species, including the Gram negative pathogen Shigella sonnei. The aim of this research is to extract and purify the compound for future structure elucidation. A mixture of compounds from 3 month old agar plates inoculated with strain KCHXC3 was extracted using ethyl acetate. The crude extract was then partially purified utilizing a Sephadex LH-20 column, followed …

The Design Of A Efficient Production And Purification Of Fibroblast Growth Factor 2, Mandeep Kaur

Chemistry & Biochemistry Undergraduate Honors Theses

Chronic wounds pose a major problem in the United States with an estimate of twenty-five million dollars a year spent on associated treatments. Growth factors can be used as a potential treatment for chronic wounds since they promote cell proliferation and angiogenesis. This study employs one specific growth factor, fibroblast growth factor 2 (FGF2) so that it could potentially be used in future treatment. Wild-type FGF2 is thermally unstable, and it has a mean elimination time of 7.6 hours. This study attempted to improve upon its stability through a mutation on the heparin binding loop. The mutation performed was K134E. …

The Use Of Hallucinogens In The Treatment Of Mental Health Disorders, Brianna Gagen

Honors College Theses

The percent of people with mental health disorders in the United States have skyrocketed over the past decade. With stigma surrounding the discussion of mental health and the symptoms associated with it, often those that are suffering do not receive sufficient treatment, as they might with a physical illness. The current, common treatment options for common psychological disorders, like depression, anxiety, and post-traumatic stress disorder, are sometimes not effective in patients, due to resistance or poor response outcomes. Consequently, in order to research alternative therapeutic approaches for mental health disorders, scientists are researching the effects of several hallucinogenic drugs in …

Design And Synthesis Of Novel Synthetic Cannabinoid 5-Hydroxy-1h-Indazole-3-Carboxamide Metabolites, Nichole Ann Pianovich

LSU New Orleans Theses and Dissertations

Since the discovery of Δ⁹-THC, the pharmaceutical industry has continuously developed synthetic analogs intending to develop compounds that exhibit the bioactivity of natural cannabinoids but are devoid of its psychoactivity. Synthetic cannabinoids often exhibit potencies significantly greater than Δ⁹-THC, as do their metabolites. Phase I metabolism of synthetic cannabinoids bearing an indazole core predominantly proceeds through oxidative transformations to produce mono-hydroxylated variants of the parent compound. Recent studies have primarily focused on N-1/C-3 hydroxylated pentyl side chains and carboxamide linked groups. These compounds often retain affinity and potency for the CB₁ receptor …

An Investigation Towards The Synthesis Of A Novel Conformationally Restricted Ethylenediamine Scaffold, Fanny Mai

Theses, Dissertations and Culminating Projects

This study reports the synthesis of a novel conformationally restricted ethylenediamine scaffold that can be explored for drug discovery. There was significant progress in synthesizing the target scaffolds, but future studies are needed to finish this synthesis. This potential ethylenediamine compound may offer new scaffolds for exploration in drug design and orexin receptor antagonists with improved selectivity for OX1R and OX2R.

Hepatocellular Carcinoma Image-Guided Intervention: Quantitative Characterization Of Reagents For Thermochemical Ablation, Emily A. Thompson

Dissertations and Theses (Open Access)

Thermochemical ablation (TCA) is a minimally invasive therapy under development for hepatocellular carcinoma, a leading cause of cancer death worldwide. TCA utilizes acid-base chemistry delivered simultaneously to induce local ablation when administered. When delivered via a mixing catheter placed directly into the tumor, acid (e.g., AcOH) and base (e.g., NaOH) react to completion at the catheter tip, producing the acetate salt, water, and releasing heat (Δ>50°C) in sufficient quantities to induce lethal osmotic and thermal stress in tumor cells. However, these two reagents are not distinguishable from tissues with noninvasive imaging modalities, which makes monitoring the delivery of TCA …

Bis(Tryptophan) Amphiphiles: Design, Synthesis And Efficacy As Antimicrobial Agents, Michael Mckeever

Dissertations

Amphiphiles play important roles in nature. These molecules contain both hydrophilic and hydrophobic regions, leading to some astonishing properties. The lipid bilayer of the cell membrane is a fascinating organization of amphiphilic phospholipids. Natural and synthetic amphiphiles, such as antimicrobial peptides, interact with the cell membrane. Such interactions can impact transport of molecules across the cell membrane, disrupting cell functions. In this work, a library of tryptophan-containing amphiphiles was synthesized and their antimicrobial properties were explored.

First, a library of bis(tryptophan) amphiphiles was synthesized. Preparation included a coupling reaction of a diamine with tryptophan residues, via their carboxy-termini, at …

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 …