Medicinal and Pharmaceutical Chemistry Commons^™

Pharmacogenetic Exploration Of Burenorphine And Related Metabolites In Umbilical Cord Blood, Amelia Monfared, Derek E. Murrell, Darshan S. Shah, Melissa Hoang, Stacy D. Brown, Sam Harirforoosh

Pharmacy Faculty Articles and Research

The goal of this study was to explore associations between single-nucleotide polymorphisms (SNPs) and umbilical cord blood concentrations of buprenorphine and its metabolites following maternal administration. This is a sub-study of a prospective observational cohort investigation which included pregnant women receiving buprenorphine for opioid use disorder during pregnancy. Following delivery, umbilical cord blood samples were collected and genotyped using a pharmacogenetic panel. The drug and metabolite concentrations were analyzed through liquid chromatography-mass spectrometry, and genetic association analysis was completed using PLINK software. The included neonates (n = 14) had a mean birth weight of 3.00 ± 0.39 kg and were …

Modulation Of Redox-Sensitive Cardiac Ion Channels, Rawan S. Orfali, Al Hassan Gamal El-Din, Varnika Karthik, Elisanjer Lamis, Vanna Xiao, Alena Ramanishka, Abdullah Alwatban, Osama Alkhamees, Ali Alaseem, Young-Woo Nam, Miao Zhang

Pharmacy Faculty Articles and Research

Redox regulation is crucial for the cardiac action potential, coordinating the sodium-driven depolarization, calcium-mediated plateau formation, and potassium-dependent repolarization processes required for proper heart function. Under physiological conditions, low-level reactive oxygen species (ROS), generated by mitochondria and membrane oxidases, adjust ion channel function and support excitation–contraction coupling. However, when ROS accumulate, they modify a variety of important channel proteins in cardiomyocytes, which commonly results in reducing potassium currents, enhancing sodium and calcium influx, and enhancing intracellular calcium release. These redox-driven alterations disrupt the cardiac rhythm, promote after-depolarizations, impair contractile force, and accelerate the development of heart diseases. Experimental models demonstrate …

Kshv Vil6 Inhibits Functional B Cell Maturation During De Novo Infection, Wajd Zakir, Jessica M. Osborn, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Despite causative links to lymphoproliferative disorders, little is known about early events governing KSHV infection in B lymphocytes. IL-6 signaling plays a critical role in KSHV-mediated disease, with human IL-6 (hIL6) levels correlating with viral load and disease progression. This dynamic is even more complex due to the coexistence of hIL6 and KSHV-encoded viral IL-6 (vIL6) in these diseases. We hypothesize that hIL6 and vIL6 play critical, separable and collective roles in the early stages of KSHV infection in B cells. In this study, we use our ex vivo model of KSHV infection in human tonsil lymphocytes to investigate the …

Surface Keratin 1, A Tumor-Selective Peptide Target In Human Triple-Negative Breast Cancer, Shih-Jing Yao, Farideh Amirrad, Elmira Ziaei, Azam Saghaeidehkordi, Moom R. Roosan, Kiumars Shamloo, Ajay Sharma, Rachita K. Sumbria, Surya M. Nauli, Christopher G. Bunick, Kamaljit Kaur

Pharmacy Faculty Articles and Research

Targeting drugs to cancer cells via overexpressed cell-surface receptors has emerged as an effective therapeutic strategy for several cancers. However, identifying cell-surface receptors that allow selective uptake of targeting ligands by cancer cells—while sparing normal cells—remains a challenge, especially for triple-negative breast cancer (TNBC), which lacks a well-defined receptor for targeted delivery. In this study, immunohistochemical (IHC) analysis revealed that human TNBC patient tissues have significantly higher levels of keratin 1 (K1) compared to normal breast tissues. Among TNBC tissues, grade 3 tumors showed significantly higher (threefold) K1 expression compared to grade 2 tumors. We analyzed human TNBC and normal …

Synthesis Of Carboxymethyl Cellulose From Nypa Fruticans For Coating Metformin On Zn-Based Metal-Organic Framework Nanohybrid As A Bionanocomposite Drug Delivery System, Delviani Delviani, Viola Giary Rizkillah Maharani, Putri Nur Shadrina, Tri Warni, Regina Wan Azizah, Indra Lasmana Tarigan, Madyawati Latief

Makara Journal of Science

Diabetes is a common and rapidly spreading disease that affects 6.6% of the world’s population. Metformin hydrochloride (HCl) is an effective oral pharmacological treatment for type 2 diabetes mellitus (T2DM) patients because of its capability to reduce glucose levels and the risk of hypoglycaemia. However, gastrointestinal sensitivities to this drug can cause diarrhoea, nausea, vomiting and stomach ache. An alternative is controlled release technology by coating metformin with carboxymethyl cellulose (CMC) and zinc-metal-organic framework (Zn-MOF) through the encapsulation method. Therefore, this study aimed to coat metformin formulations using CMC in a Zn-MOF to control release into the body and minimise …

Determination Of The Anti-Inflammatory Activity Of The Methanolic Leaf Extract Of Strelitzia Reginae (Strelitziaceae), Lyannah Deign Hearty Delantar Hinol, Miflor De La Cerna, Decethree Gocela, Aymah Macalonto, Junnin Gay Garay

Pacific Journal of Health

Inflammation is a biological response that, if unregulated, can contribute to various health disorders. The search for new anti-inflammatory agents has led researchers to explore the medicinal potential of Strelitzia reginae, commonly known as the Bird of Paradise. This study aimed to determine the phytochemical composition and anti-inflammatory activity of the methanolic leaf extract of S. reginae. Phytochemical screening confirmed the presence of alkaloids, flavonoids, terpenoids, phenols, saponins, and steroids, while tannins were absent. The Croton Oil-Induced Ear Edema Assay in Swiss albino mice was used to assess anti-inflammatory activity, with Indomethacin as a positive control. Acute oral …

Impact Of Stereochemical Replacement On Activity And Selectivity Of Membrane-Active Antibacterial And Antifungal Cyclic Peptides, Sandeep Lohan, Anastasia G. Konshina, Eman H. M. Mohammed, Naiera M. Helmy, Srishhti K. Jha, Rakesh Kumar Tiwari, Innokentiy Maslennikov, Roman G. Efremov, Keykavous Parang

Pharmacy Faculty Articles and Research

Herein, we report a library of 7-mer macrocyclic peptides designed by systematically replacing one, multiple, or all L-amino acids with their D-isomers in our previously identified hit compounds. Lead peptides, 15c and 16c, showed broad-spectrum activity against bacteria (Gram-positive minimum inhibitory activity (MIC 1.5–6.2 µg/mL and Gram-negative MIC 6.2–25 µg/mL) and fungi (MIC = 3.1–25 µg/mL). Additionally, peptides 15c and 16c showed rapid kill kinetics and biofilm degradation potential against both bacteria and fungi, while resistance development was not observed. The antimicrobial effect of these macrocyclic peptides was attributed to their membranolytic action, which was confirmed by calcein dye …

Multidrug Resistance: Are We Still Afraid Of The Big Bad Wolf, Abdulelah Alhazza, Adenike Oyegbesan, Emira Bousoik, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

After the era of multidrug resistance (MDR) against cytotoxic chemotherapy, the development of resistance against newly developed molecularly targeted drugs also seems inevitable. While the mechanisms involved in resistance against these two categories of anticancer drugs are different, the principles are similar: inherent resistance (also known as primary resistance) is a result of heterogeneity in cancer cells where a subpopulation of the cells do not show a favorable initial response to the drug, while acquired resistance (or secondary resistance), as the name suggests, is developed after repeated treatments due to the plasticity of cancer cells. Despite the introduction of a …

Engineering Lipid–Polymer Nanoparticles For Sirna Delivery To Cancer Cells, Arthur Manda, Abdulelah Alhazza, Hasan Uludağ, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

Background: RNA interference (RNAi) is a powerful tool that can target many proteins without the expensive and time-consuming drug development studies. However, due to the challenges in delivering RNA molecules, the potential impact of RNAi approaches is yet to be fully realized in clinical settings. Lipid nanoparticles (LNPs) have been the most successful delivery system for nucleic acids, but targeted delivery to a solid tumor still eludes the developed LNPs. We hypothesized that specially designed low-molecular-weight PEIs can partially or completely replace the ionizable lipids for more accommodating vehicles due to the structural flexibility offered by polymers, which could …

Molecular Insights Into The Role Of Estrogen Receptor Beta In Ecdysterone Mediated Anabolic Activity, Syeda Sumayya Tariq, Madiha Sardar, Muhammad Shafiq, Hendrick Heinz, Mohammad Nur-E-Alam, Aftab Ahmad, Zaheer Ul-Haq

Pharmacy Faculty Articles and Research

Ecdysterone, often dubbed a “natural steroid,” has garnered significant attention among athletes for its reputed growth-promoting and anabolic properties. Unlike synthetic anabolic steroids, which are classified as controlled substances, ecdysteroids remain largely unregulated in many countries and are widely marketed as dietary supplements. Notably, ecdysterone has been included in the World Anti-Doping Agency (WADA) monitoring program, highlighting its potential impact on athletic performance and raising questions about its regulation. Emerging evidence indicates that, unlike traditional anabolic steroids that act primarily via the Androgen Receptor (AR), ecdysterone’s anabolic effects may be mediated through Estrogen Receptors (ERs), particularly Estrogen Receptor beta (ERβ). …

An Exploratory Pharmacogenetic Pilot Study Of Two Reverse Transcriptase Inhibitors, Tenofovir Alafenamide Fumarate And Tenofovir Disoproxil Fumarate, Derek E. Murrell, Benjamin C. Kennard, Maria E. Bertoni, David B. Cluck, Jonathan P. Moorman, Stacy D. Brown, Keshang Wang, Michelle M. Duffourc, Sam Harirforoosh

Pharmacy Faculty Articles and Research

Background and Objectives

The nucleoside reverse transcriptase inhibitors tenofovir alafenamide fumarate and tenofovir disoproxil fumarate are frequently employed in treating human immunodeficiency virus. Further, each form of tenofovir requires laboratory monitoring to determine efficacy and tolerability among patients. This study sought to investigate the relationship, if any, of single nucleotide polymorphisms (SNPs) and selected clinical parameters.

Methods

The study population, predominantly Caucasian males with a median age of 53.0 years [interquartile range 46.0–59.0], was assayed for genetic variations using an iPLEX ADME PGx Pro v1.0 Panel.

Results

Although several SNP relationships were found with both forms of tenofovir, many of …

Targeting Neuronal Nitric Oxide Synthase (Nnos) As A Novel Approach To Enhancing The Anti-Melanoma Activity Of Immune Checkpoint Inhibitors, Anika R. Patel, Shirley Tong, Kate Alison Lozada, Amardeep Awasthi, Richard B. Silverman, Jennifer Totonchy, Sun Yang

Pharmacy Faculty Articles and Research

Background and Objectives: Neuronal nitric oxide synthase (nNOS) overexpressed in melanoma plays a critical role in disease progression. Our previous studies demonstrated that nNOS inhibitors exhibited potent anti-melanoma activity and regulated PD-L1 expressions in the presence of interferon-gamma (IFN-γ). However, the role of nNOS in the melanoma immune response has not been well defined. Methods: Changes in gene expression profiles after nNOS inhibitor treatment were determined by transcriptomic analysis. A melanoma mouse model was used to determine the effects of nNOS inhibition on peripheral T cells and the in vivo anti-tumor activity of combining nNOS inhibitors with immune …

Integrative Computational Modeling Of Distinct Binding Mechanisms For Broadly Neutralizing Antibodies Targeting Sars-Cov-2 Spike Omicron Variants: Balance Of Evolutionary And Dynamic Adaptability In Shaping Molecular Determinants Of Immune Escape, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we conducted a comprehensive analysis of the interactions between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and four neutralizing antibodies—S309, S304, CYFN1006, and VIR-7229. Using integrative computational modeling that combined all-atom molecular dynamics (MD) simulations, mutational scanning, and MM-GBSA binding free energy calculations, we elucidated the structural, energetic, and dynamic determinants of antibody binding. Our findings reveal distinct dynamic binding mechanisms and evolutionary adaptation driving the broad neutralization effect of these antibodies. We show that S309 targets conserved residues near the ACE2 interface, leveraging synergistic van der Waals and electrostatic interactions, while S304 focuses on …

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, …

Application Of Bioactive Materials Primary Cilia As A Novel Delivery Vehicle, Ayan K. Barui, Farideh Amirrad, Vansh Goel, Sharareh Ohadi, Rajasekharreddy Pala, Ashraf M. Mohieldin, Andromeda M. Nauli, Surya M. Nauli

Pharmacy Faculty Articles and Research

Primary cilia are hair-like structured cell organelles functioning as cellular antennae with chemosensory and mechanosensory roles. Dysfunction of cilia results in ciliopathies, including renovascular diseases (polycystic kidneys, hypertension, aneurysm), mental impedances (Alzheimer's disease, Parkinson's disease, dementia), metabolic diseases (obesity, developmental skeleton defects), blindness, and so on. With a diameter of 150 nm, cilia can be cleaved, released and circulated in the body as injury biomarkers. We here assessed the potential use of isolated cilia as a novel delivery vehicle. Cilia were isolated from renal epithelial cells, and a specific-targeting chemotherapeutic was designed on the cilia. The data show a remarkable …

A Review Of Praziquantel Resistance In Schistosomes And The Future Of Schistosomiasis Control, Gabriela G. Eastham

Senior Honors Theses

Schistosomiasis is a group of both acute and chronic parasitic trematode infections of the genus Schistosoma. Praziquantel (PZQ) has been the drug of choice to treat schistosomiasis for decades. Though it is effective against all three clinically relevant species, heavy reliance on PZQ has led to concerns of schistosome resistance, especially in areas that have implemented this drug in mass drug administration (MDA) programs. Although there is currently insufficient evidence to conclude that schistosomes are becoming resistant to PZQ on a large scale, other control methods are a necessity to best treat and eliminate schistosomiasis. This article summarizes the …

Design And Structural Basis Of Selective 1,4-Dihydropyridine Inhibitors Of The Calcium-Activated Potassium Channel KCa3.1, Seow Theng Ong, Young-Woo Nam, Joshua A. Nasburg, Alena Ramanishka, Xuan Rui Ng, Zhong Zhuang, Stephanie Shee Min Goay, Hai M. Nguyen, Latika Singh, Vikrant Singh, Alicia Rivera, M. Elaine Eyster, Yang Xu, Seth L. Alper, Heike Wulff, Miao Zhang, K. George Chandy

Pharmacy Faculty Articles and Research

The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K+ channel K_Ca3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K_Ca3.1 with an IC50 of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of …

Determining The Bioaccumulation Of Minor Cannabinoids In Zebrafish Larvae, Kamdyn A. Holt

Honors Theses

Due to the increasing prevalence of cannabis product availability and usage in the modern United States, particularly among pregnant individuals, evaluating the bioaccumulation of minor cannabinoids to further understand the adverse effects of cannabinoids during early development is critical. This study quantitated the uptake of eight minor cannabinoids ((∆8-tetrahydrocannabinol (∆8-THC), ∆9-THC, ∆10-THC, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), tetrahydrocannabivarin (THCV), and hexahydrocannabinol (HHC)) in zebrafish larvae following water-borne 2 µM exposures from 6 to 96 hours post fertilization (hpf). Larvae were homogenized at 96 hpf and analyzed using a gas chromatography- mass spectrometry (GC-MS) method developed in this study. Bioconcentration …

Molecular Insights Into Antibiofilm Inhibitors Of Streptococcus Mutans Glucosyltransferases Through In Silico Approaches, Lubna Atta, Ali Raza Siddiqui, Mamona Mushtaq, Sajida Munsif, Mohammad Nur-E-Alam, Aftab Ahmad, Zaheer Ul-Haq

Pharmacy Faculty Articles and Research

Streptococcus mutans, a primary cariogenic bacterium, plays a central role in dental caries, one of the most widespread chronic diseases globally. Glucosyltransferases (GTFs) are key virulence factors in this process, as they synthesize extracellular polysaccharides that contribute to biofilm formation and pathogenicity. Targeting GTFs has emerged as a promising strategy for preventing dental caries, with previous studies demonstrating its potential efficacy. This study builds on our prior work by providing detailed molecular insights into the binding modes of previously identified GTF inhibitors. Using computational tools, including density functional theory, molecular docking, and molecular dynamics simulations, we examined the binding …

Cryo-Em Structures Of The Small-Conductance Ca2+-Activated KCa2.2 Channel, Young-Woo Nam, Dohyun Im, Ana Santa Cruz Garcia, Marios L. Tringides, Hai Minh Nguyen, Yan Liu, Razan Orfali, Alena Ramanishka, Grigore Pintilie, Chih-Chia Su, Meng Cui, Diomedes E. Logothetis, Edward W. Yu, Heike Wulff, K. George Chandy, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated K+ (K_Ca2.1-K_Ca2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the K_Ca2.2 channel in complex with calmodulin and Ca²⁺, alone or bound to two small molecule inhibitors, at 3.18, 3.50, 2.99 and 2.97 angstrom resolution, respectively. Extracellular S3-S4 loops in β-hairpin configuration form an outer canopy over the pore with an aromatic box at the canopy’s center. Each S3-S4 β-hairpin is tethered to the selectivity filter in the neighboring subunit by inter-subunit hydrogen bonds. This hydrogen bond network flips the aromatic residue (Tyr362) in …