Medicinal and Pharmaceutical Chemistry 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, …

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 …

Brain Endothelial Cells As Phagocytes: Mechanisms And Implications, Rudy T. Chang, Mark J. Fisher, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Brain microvascular endothelial cells (BECs) lining the brain capillaries form the anatomical site of the blood-brain barrier (BBB), providing a highly selective barrier to support brain homeostasis and function. While the BBB acts as a barrier to immune cells and pathogens under normal conditions, BECs can facilitate their entry into the CNS via a phagocytosis-like mechanism. A similar process is now increasingly reported for a diverse set of cargos, resulting in the categorization of BECs as “non-professional” phagocytes and redefining the conventional view that these cells are functionally non-phagocytic. This review aims to summarize research demonstrating the capacity of BECs …

Antituberculosis Potential Of Borrelidin Derivatives: An In Silico Molecular Docking And Molecular Dynamic Approach, Teni Ernawati, Donny Ramadhan, Faris Hermawan, Sasmito Wulyoadi, Bambang Marwoto, Ahmad Wibisana, Bambang Srijanto

The Thai Journal of Pharmaceutical Sciences

Background: The present tuberculosis (TB) treatment requires a significant time commitment, often lasting from 6 months to 2 years, with strict daily adherence. Non-compliance leads to drug resistance and suboptimal outcomes. Present research indicates that borrelidin shows potential activity against Mycobacterium tuberculosis, including strains that are resistant to first-line medications. Borrelidin has shown remarkable activity against M. tuberculosis H37Rv, with a minimum inhibitory concentration value of 3.12 μg/mL. Therefore, investigating the inhibition activity of borrelidin derivatives was essential for finding new anti-TB candidates. Objectives: This study aims to investigate the effects of 31 borrelidin derivative compounds …

The Antioxidant And Antiaging Activity Of Fig (Ficus Carica Linn) Leaf Ethanolic Extract In Vitro, Aji Winanta, Novita Zulaekhah, Perdana Priya Haresmita, Annisa Krisridwany, Rifki Febriansah, Inka Aprissa

The Thai Journal of Pharmaceutical Sciences

Background: Human organ systems can experience the aging process, one of which is the aging of the skin, characterized by dry, rough, or scaly skin, dullness, dark spots, and wrinkles. Previous studies have found that fig leaves contain compounds that have the potential to be anti-aging.
Objectives: This study aimed to determine the potential of fig leaves (Ficus carica Linn) as an anti-aging agent by examining their antioxidant activity, elastase inhibition, and antioxidative stress activity against hydrogen peroxide (H₂O₂). Materials and Methods: The phytochemicals in fig leaf ethanol extract were identified using phytochemical screening tests, …

Penghambat Kanal Kalsium Sebagai Kontrol Glukosa Darah Pada Insulinoma: Sebuah Laporan Kasus, Nadhira Nizam, Ryan Tresna Putra, Anshari Saifuddin Hasibuan

Jurnal Penyakit Dalam Indonesia

Insulinoma is a rare neuroendocrine tumor of the pancreas arising from β-cells, leading to excessive insulin secretion and resultant hypoglycaemia. Surgical resection is the first-line treatment for insulinoma, but when surgery is not feasible, medical therapy is an important option. Calcium channel blockers (CCBs) such as verapamil can inhibit insulin release from β-cells and have been proposed as an adjunct therapy to help control blood glucose levels in insulinoma. We report a 43-year-old man who presented to the emergency department with decreased consciousness due to hypoglycaemia. His capillary blood glucose at home was 35 mg/dL, about 8 hours after his …

Phytochemical Analysis And In Vivo Anticancer Effect Of Becium Grandiflorum: Isolation And Characterization Of A Promising Cytotoxic Diterpene, Christeen Fahim, Maha R. A. Abdollah, Rola Milad, Nehal Sabry, Noha Swilam

Pharmacy

Background:Becium grandiflorum is a fragrant perennial shrub of the Lamiaceae family. Objectives: The current study aimed to explore the cytotoxic potential of the nhexane fraction from Becium grandiflorum aerial parts and, further, isolate its major diterpene and conduct in vitro and in vivo anticancer activities along with its molecular mechanism and synergy with doxorubicin. Methods: The hydroalcoholic extract of Becium grandiflorum aerial parts was fractionated, and the n-hexane fraction was analyzed via GC-MS. The major isolated diterpene, 18-epoxy-pimara-8(14),15-diene (epoxy-pimaradiene), was quantified using UPLC-PDA. Cytotoxicity assays were conducted on HCT-116, MCF-7, MDA-MB- 231, and HepG2 cell lines. The synergistic effect with …

Cracking The Code Of Hbv Persistence: Cutting-Edge Approaches To Targeting Cccdna In Chronic Hepatitis B With Or Without Pyogenic Liver Abscesses, Umar Saeed, Zahra Zahid Piracha, Mahmood Khan, Muhammad Nouman Tariq, Syed Shahan Gilani, Muhammad Raza, Rakshana Munuswamy, Naveen Bose, Dilber Uzun Ozsahin, Ilker Özşahin, Surya M. Nauli

Pharmacy Faculty Articles and Research

Chronic Hepatitis B Virus (HBV) infection remains a formidable global health challenge, driving severe liver complications such as hepatocellular carcinoma (HCC) and pyogenic liver abscesses (PLA). At the core of HBV persistence lies covalently closed circular DNA (cccDNA), a viral reservoir that fuels ongoing infection despite antiviral treatments. This review highlights molecular mechanisms governing cccDNA formation, maintenance, and clearance, spotlighting innovative therapeutic strategies to disrupt this key viral element. We explore cutting-edge approaches, including epigenetic modulation to silence cccDNA, RNA interference (RNAi) for viral RNA degradation, and CRISPR/Cas genome editing to excise cccDNA directly. Additionally, emerging antiviral therapies and immunotherapies, …

Development Of A Multi-Epitope Peptide Vaccine Against Monkeypox Virus: Immunoinformatics Analysis For South East Asian Hla Alleles, Nelson Chandra, Mochammad Aqilah Herdiansyah, Viol Dhea Kharisma, Arif Nur Muhammad Ansori, Arli Aditya Parikesit

Makara Journal of Science

The monkeypox virus (MPXV), a DNA virus causing zoonotic disease, poses major global public health challenges, with mortality rates between 3%–6%. Although smallpox vaccines provide partial cross-protection, there is a critical need for a dedicated, effective monkeypox (mpox) vaccine. This study aimed to design a multi-epitope peptide-based vaccine specifically adapted to the HLA allele profiles common in Southeast Asian populations, where MPXV cases are rising. Using immunoinformatics, we screened for and detected B and T cell epitopes from the MPXV cell surface antigen and IFN-alpha/beta receptor proteins. The vaccine design was validated through a rigorous evaluation of its antigenicity, immunogenicity, …

Overview Of Chromatographic Methods Of Analysis Of Penicillins In Food Matrices Of Animal Origin, Tarekegn Tadesse Unade, Gudeta Duga Geresu, Pawar A. Krishnamanjari

International Journal of Health and Allied Sciences

Penicillins are β-lactam antibiotics indicated for preventing and treating diseases in veterinary medical practice. Improper use of these antibiotics in animals may result in residues in foodstuffs such as milk, egg, and meat, which can cause unwanted effects like allergy, and development of bacterial resistance. So, it is important to regulate the use of penicillins in foodstuffs of animal origin. Regulatory bodies in different countries established maximum residue levels to be allowed in food matrices. To address the regulatory requirements, food matrices need to be investigated with proper methods of analysis. Several analytical methods were developed and validated to determine …

In-Silico Modeling And Characterization Of Kcc2 Protein Interaction With A Small Molecule Direct Agonist Identifies Potential Binding Sites For Modulating Behaviors Associated With Substances Of Abuse, William Hai Dang Ho, Alfred Amendolara, Kenyon Mitchell, Jaden Miner, Ruth Northcott, Braxton Bingham, Andrew J. Payne

Annual Research Symposium

Purpose

KCC2 is a potassium-chloride cotransporter that plays a critical role in neuronal function by regulating GABAergic signaling via chloride gradients. Maintaining this concentration gradient is crucial for balancing excitation and inhibition in the brain. While KCC2 dysregulation has been implicated in epilepsy and seizures, recent studies suggest that KCC2 inhibition results in phenotypes mirroring those seen in chronic opioid dependence. As such, increasing evidence support KCC2 being a potential therapeutic target for modulating behaviors associated with substances of abuse. Currently, only a few direct small molecule agonists against KCC2 have been reported, and no definitive active site on the …

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 …

6,7-Dichloro-1h-Indole-2,3-Dione-3-Oxime Functions As A Superagonist For The Intermediate-Conductance Ca2+-Activated K+ Channel KCa3.1, Joshua A. Nasburg, Kyle C. Rouen, Connor J. Dietrich, Heesung Shim, Miao Zhang, Igor Vorobyov, Heike Wulff

Pharmacy Faculty Articles and Research

NS309 (6,7-dichloro-1H-indole-2,3-dione-3-oxime) is widely used as a pharmacological tool to increase the activity of small- and intermediate-conductance calcium-activated potassium channels. NS309 is assumed to function as a positive allosteric gating modulator. However, its binding site and the molecular details of its action remain unknown. Here, we show that NS309 has a profound effect on the calcium-dependent gating of the intermediate-conductance Ca2+-activated K+ channel KCa3.1. In inside-out experiments, 10 μM NS309 shifted the calcium EC50 from 430 to 31 nM. In whole-cell experiments, changing free intracellular calcium from 250 nM to 3 μM decreased the EC50 of …

Crosstalk Between Nnos/No And Cox-2 Enhances Interferon-Gamma-Stimulated Melanoma Progression, Anika Patel, Shirley Tong, Moom R. Roosan, Basir Syed, Amardeep Awasthi, Richard B. Silverman, Sun Yang

Pharmacy Faculty Articles and Research

Background/Objectives: Interferon gamma (IFN-γ) in the melanoma tumor microenvironment plays opposing roles, orchestrating both pro-tumorigenic activity and anticancer immune responses. Our previous studies demonstrated the role of neuronal nitric oxide synthase (nNOS) in IFN-γ-stimulated melanoma progression. However, the underlying mechanism has not been well defined. This study determined whether the nNOS/NO and COX-2/PGE2 signaling pathways crosstalk and augment the pro-tumorigenic effects of IFN-γ in melanoma. Methods: Bioinformatic analysis of patient and cellular proteomic data was conducted to identify proteins of interest associated with IFN-γ treatment in melanoma. Changes in protein expression were determined using various analytical techniques including …

Safety Of Omadacycline Versus Standard-Of-Care Oral Antibiotic Treatment For Bone And Joint Infections: Interim Results From An Open-Label, Non- Inferiority, Randomized Controlled Trial, Amy Y. Kang, Guarina Garcia Delgado, Donna Phan Tran, Evelyn A. Flores, Vanessa Romo-Kozan, Isabel Payan, Loren G. Miller

Pharmacy Faculty Articles and Research

Background

The incidence of bone and joint infections (BJIs) continues to increase, and existing oral BJI antibiotics have limitations. Omadacycline may be a potential treatment option for BJI treatment due to activity against doxycycline-resistant S. aureus and ESBL-producing Enterobacterales for which there are often no viable oral options. However, the safety of omadacycline in this setting is poorly defined.

Methods

We performed an open label, randomized, controlled clinical trial of adults with BJIs in the outpatient setting. Participants were randomized to omadacycline-containing regimen (omadacycline 300mg po daily) or Standard-of-Care (SOC) antibiotics. Adjunctive antibiotics were permitted in addition to omadacycline. Safety …