Ammena Y. Binsaleh

Background/Objectives: Methionine adenosyltransferase 2A (MAT2A) has emerged as a promising therapeutic target in cancers harboring methylthioadenosine phosphorylase (MTAP) deletion. However, the development of potent, drug-like MAT2A inhibitors with favorable pharmacokinetic profiles remains challenging. This study aimed to design, synthesize, and evaluate a library of benzofuran-based oxadiazole derivatives as novel MAT2A inhibitors and to elucidate their molecular basis of action through integrated computational studies. Methods: A series of benzofuran-based oxadiazole derivatives (10a–10j and 16–19) was designed, synthesized, and characterized by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). All compounds were evaluated for MAT2A inhibitory activity, with AZ-28 used as the reference inhibitor. The most active compounds were subjected to molecular docking, 200 ns molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and in silico ADME/toxicity prediction. No preregistration was applicable, and no animals were used in this study. Results: The synthesized compounds exhibited a broad range of MAT2A inhibition, with IC₅₀ values from 0.0116 ± 0.0020 to 28.77 ± 1.79 μM, benchmarked against AZ-28 (IC₅₀ = 0.0419 ± 0.0032 μM). Compounds 10g (IC₅₀ = 0.0116 ± 0.0020 μM), 10a (IC₅₀ = 0.0883 ± 0.0060 μM), and 19 (IC₅₀ = 0.158 ± 0.015 μM) were the most potent. Docking revealed favorable binding orientations within the MAT2A active site, supported by hydrogen-bonding and hydrophobic interactions. MD simulations showed stable protein–ligand complexes with favorable RMSD profiles, and binding free-energy calculations supported complex stability. DFT analyses (HOMO–LUMO and MEP) provided insight into electronic properties and reactive sites. Furthermore, in silico ADME and toxicity assessments provided preliminary insights into the drug-likeness and pharmacokinetic properties of the studied compounds. Nevertheless, these computational predictions remain preliminary and require experimental validation. Conclusions: Compounds 10g, 10a, and 19 are promising MAT2A inhibitors, with 10g identified as the most favorable lead. These computational predictions remain preliminary and require experimental validation. Further pharmacokinetic, toxicological, and in vivo studies of 10g are warranted.

Background: Urothelial carcinoma exhibits molecular heterogeneity, high recurrence, and progression rates, and is poorly diagnosed and treated. Transcriptomic and systems-biology analyses can detect dysregulated genes, signaling pathways, and interactions of immune cells. Proposed biomarkers, however, have not been validated, evaluated, and confirmed to be cell-type specific, limiting their potential for clinical translation. Methods: The transcriptomic data in GSE13507 were used to identify features of differential expression, functional enrichment, protein interaction network, and hub genes. Findings were assessed by using external validation, ROC and machine learning models, immune-infiltration analysis, single-cell expression profiling, and survival analysis. Results: In total, 7459 differentially expressed probes were detected, and pathways involved in immunity and cytokines were noted to be enriched. The best diagnostic performance was observed with IL6ST (AUC 0.927), LIFR (AUC 0.921), and JAK1 (AUC 0.843). We found a correlation between hub genes and infiltration of immune cells, and a difference in single-cell distribution; however, none of them was shown to have a significant association with overall survival. Conclusions: The IL-6/JAK/STAT hub gene network was highly diagnostic and immune-relevant in urothelial carcinoma and had limited prognostic significance. The three most promising candidates were IL6ST, LIFR, and JAK1. The genes identified in this study could be validated in tumor-normal pairs and in prospective clinical samples of future studies, accompanied by protein levels and functional studies.

Background: Montelukast is commonly prescribed as an adjunctive controller therapy in pediatric asthma, particularly among children with mild-to-moderate disease, allergic comorbidities, or challenges related to inhaled therapy adherence. However, real-world evidence regarding asthma-related outcomes, adherence patterns, and safety in routine pediatric practice remains limited. Objective: To evaluate asthma-related clinical outcomes, treatment adherence, and safety observations associated with montelukast therapy among pediatric patients with mild-to-moderate asthma in routine clinical practice. Methods: This retrospective observational pre–post study included pediatric patients aged 2– 14 years with physician-documented mild-to-moderate asthma who received montelukast therapy for at least six consecutive months at Prince Sultan Military Medical City, Riyadh, Saudi Arabia, between January 2023 and May 2024. Data extracted from electronic medical records included asthma exacerbations, systemic corticosteroid use, rescue medication use, treatment adherence, and documented adverse events before and after montelukast initiation. Paired and comparative statistical analyses were performed to evaluate changes in asthma-related outcomes and factors associated with clinical improvement. Results: A total of 149 pediatric patients were included, with a median age of 8 years; 69.8% were male. Montelukast initiation was significantly associated with observed reductions in asthma exacerbations from one episode (range:0– 12) before treatment to zero episodes (range: 0– 6) after treatment (p=001), systemic corticosteroid use from one corticosteroid course (range − 6) before treatment to zero courses (range: 0– 6) following montelukast therapy (p = 0.006), and reduced rescue medication requirements. Physician-documented clinical improvement was observed in 61.1% of patients. Treatment adherence was strongly associated with improved clinical outcomes. Documented adverse events were uncommon, with behavioral symptoms reported in 2% of patients and no serious treatment-related adverse events identified during follow-up. Conclusion: Montelukast therapy was associated with favorable asthma-related outcomes and was generally well tolerated. Treatment adherence appeared to play an important role in clinical improvement. However, given the retrospective observational design and absence of a control group, prospective controlled studies are needed to further evaluate the long-term effectiveness and safety of montelukast in pediatric asthma management.

Background Pharmacogenomics-guided therapy is a promising approach for optimizing antihypertensive treatment response; however, robust real-world data from South Asian and particularly Pakistani populations remain scarce. Understanding genotype-drug response relationships in this underrepresented population is essential to inform context-specific precision prescribing strategies. Objective To evaluate associations between pharmacogenomics variants and antihypertensive therapy response using electronic health record (EHR) data from Khyber Pakhtunkhwa (KPK) patients, and to assess the incremental predictive value and practical limitations of genotype-based stratification in routine clinical care. Methods This retrospective cohort study analyzed 1,247 hypertensive patients treated at Kuwait Teaching Hospital (KTH), Peshawar, between January 2023 and August 2025. Hypertensive adults initiating antihypertensive monotherapy with at least 12 months of EHR follow-up and available genotyping results were included to minimize misclassification of treatment response. Five pharmacogenomics variants (CYP3A5 rs776746, ADD1 rs4961, NEDD4L rs4149601, ADRB1 rs1801253, and ACE rs4340) were genotyped using TaqMan assays. Primary outcomes were systolic blood pressure (SBP) reduction and target BP achievement (< 140/90 mmHg), analyzed using ANOVA, multivariable logistic regression, and receiver operating characteristic (ROC) curve analysis. Multiple testing was addressed using a Bonferroni-corrected significance threshold (α = 0.002) for variant-drug class associations, and model discrimination was internally validated using bootstrap resampling (1,000 iterations). Results Mean patient age was 63.1 ± 11.5 years; 661 (53.0%) were female. Baseline SBP/DBP were 157.1 ± 18.8/91.7 ± 11.1 mmHg. Calcium channel blockers (CCBs) produced greater SBP reduction than other classes (22.32 ± 8.78 vs. 19.68 ± 8.67 mmHg, t = 4.43, p = 1.0 × 10^− 5; overall drug-class ANOVA F = 5.27, p = 3.3 × 10^− 4, Bonferroni-significant). The CYP3A5 rs776746 *3/*3 genotype was associated with enhanced CCB response (23.96 ± 8.79 vs. 19.78 ± 8.17 mmHg, p = 9.7 × 10^− 5), and the ADD1 rs4961 GG genotype with superior diuretic response (24.02 ± 8.84 vs. 17.66 ± 8.69 mmHg, p = 1.7 × 10^− 6); both associations remained significant after Bonferroni correction. On direct recalculation from raw genotype counts, four of five variants deviated from Hardy-Weinberg equilibrium (CYP3A5 p = 0.0058, NEDD4L p = 0.0146, ADRB1 p < 0.0001, ACE p = 0.0379), while ADD1 remained in equilibrium (p = 0.554). In multivariable logistic regression, older age (aOR = 1.019, 95% CI 1.007–1.031), lower baseline SBP (aOR = 0.915, 95% CI 0.906–0.925), and absence of diabetes (aOR = 0.670 for diabetes, 95% CI 0.499–0.901) were independent predictors of target BP achievement; CCB therapy (aOR = 1.362, 95% CI 0.975–1.902) and favorable CYP3A5/ADD1 genotypes (aOR 1.14 each) showed positive but non-significant trends. The model achieved an AUC of 0.847, with a bootstrap-derived optimism-corrected AUC of 0.841 (95% CI 0.823–0.866). Conclusions Real-world EHR data from Khyber Pakhtunkhwa reveal significant genotype-treatment response associations for CCB and diuretic therapy in an underrepresented South Asian population. However, the extensive Hardy-Weinberg disequilibrium observed across four of five variants indicates that population stratification and/or genotyping considerations must be more fully accounted for, and together with the observational design and lack of external validation, these findings should be regarded as hypothesis-generating rather than sufficient grounds for routine clinical implementation of pharmacogenomics-guided antihypertensive therapy. Graphical Abstract

Atrial fibrillation (AF) affects about 1 to 2% of the general population and increases the risk of ischaemic stroke by 5-fold. Non-valvular atrial fibrillation (NVAF), the most common form of AF, i...

Background: Use of generic medicines enhances drug affordability and accessibility. The aim if this study was to assess the association between pharmacy educational programs and final-year pharmacy students’ perceptions and confidence in generic medicines. Methodology: A cross-sectional survey was conducted in July 2025 among 248 fifth-year pharmacy students enrolled in two educational programs at Badr University in Cairo (BUC): the Pharm D Clinical Pharmacy program and the Pharm D program. The survey assessed knowledge of generic equivalency and beliefs regarding the quality, safety, and effectiveness of generic medicines compared to those of brand medications. Descriptive statistics, Chi-square test, and confidence intervals were used for data analysis, with a significance level set at p < 0.050. Results: Awareness of generic drug therapeutic equivalence was significantly higher in the Pharm D program than in the Pharm D clinical program (93.4% vs. 70.3%; p = 0.010; 95% CI: 0.02–0.10; Cramér’s V = 0.35). However, a notable proportion in both groups reported limited education regarding detailed bioequivalence issues. A substantial proportion of students in both programs reported the need for enhanced education about safety and efficacy of generics, especially in the clinical program (89.3% vs. 68.9%, p = 0.010; 95% CI: 0.02–0.10; Cramér’s V = 0.33). Conclusion: We identified significant differences in knowledge and attitudes regarding generic drugs between the two pharmacy programs. These differences are likely associated with variations in curriculum structure and content. Although general knowledge appears adequate, the Pharm D Clinical Pharmacy program may benefit from more targeted educational tracks about bioequivalence, quality assurance, and pharmacoeconomics that may better prepare future pharmacists to confidently recommend generic medications. Further multicenter studies are recommended to validate these findings.

Background: Hormone receptor-positive (HR+), Human Epidermal growth factor Receptor 2 (HER2-negative) metastatic breast cancer (MBC) represents a substantial proportion of breast cancer cases in Saudi Arabia. Despite the established efficacy of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, particularly Palbociclib, in randomized control trials, real-world data from local institutions in Saudi Arabia remain limited. Objectives: This study aimed to evaluate progression-free survival (PFS), overall survival (OS), and toxicity profile among HR+, HER2-negative MBC female patients treated with Palbociclib at King Fahad Medical City (KFMC). Methods: A retrospective study was conducted on female patients with HR+/HER2-negative MBC treated with oral palbociclib combined with endocrine therapy (ET) at KFMC between January 2021 and September 2024. Data were collected from electronic health records. Descriptive statistics were conducted using mean for continuous variables and frequency for categorical variables. Survival analyses were conducted using Cox regression, log-rank tests and Kaplan–Meier analysis. Results: A total of 169 female patients with HR+/HER2− MBC were included. In the first-line setting, the median PFS was 20.14 months (95% CI: 14.65–30.49), compared with 11.3 months (95% CI: 7.98–not estimable) in the second-line setting. For OS, the median OS values were 53.1 months (95% CI: 41.2–not estimable) in the first-line group and 23.7 months (95% CI: 18.5–not estimable) in the second-line group. Significant predictors of shorter PFS included age, Body Mass Index (BMI), type of ET, cancer type, line of therapy, family history of cancer, and history of VTE. Visceral metastasis (HR = 3.087; p = 0.0229) and ECOG performance status of 4 (HR = 13.86; p = 0.0156) were associated with significantly shorter OS. The most common hematological adverse events (AEs) were neutropenia (45.6%), followed by anemia (5.9%), leukopenia (5.3%), and back pain (5.3%). Most toxicities were managed with dose reduction, holding treatment, or supportive care. Conclusions: Palbociclib demonstrated favorable survival outcomes and a manageable safety profile, with neutropenia being the most common AE. This study provides region-specific real-world evidence supporting the use of Palbociclib in HR+/HER2− MBC. These findings align with global trial data and highlight the importance of individualized treatment in clinical practice.

Abnormal protease activity plays a crucial role in replication and survival of SARS-CoV-2, the causative agent of COVID-19. The main protease has therefore emerged as a vital therapeutic target in the discovery of antiviral drugs. In this study, a novel series of Quinoline-based scaffolds were synthesized via a multi-step sequence. The novelty of this work lies in the development of a quinoline-based molecular framework specifically tailored for Mpro inhibition, combined with a comprehensive structure–activity relationship (SAR) investigation integrating both experimental and computational approaches. The synthesized molecules were structurally confirmed by ¹ H NMR, [ ]C NMR and HRMS analysis. The compounds were evaluated for their inhibitory activity against SARS-CoV-2 and several derivatives demonstrated promising potency. Particularly, compounds 9a (IC[ ] nM), 9 g (IC[ ] nM) and 9i (IC[ ] nM) exhibited strong inhibitory effects as compared to the standard reference inhibitor. Furthermore, molecular docking and computational analysis provided insight into the binding interactions and supported the observed experimental results by revealing key hydrogen bonding and [ ]–[ ] stacking interactions with catalytic residues in the enzyme’s active site. These results suggest that the synthesized Quinoline-based scaffolds are promising lead candidates for further optimization in the development of effective antiviral agents against SARS-CoV-2.

Upon careful re-examination of the RCSB entry for PDB ID: 7C36 prompted by an insightful reader, the authors confirm that this structure corresponds to RBMS1 (UniProt: P29558), a single-stranded DNA-binding protein involved in regulation of the c-MYC promoter, and not to the human c-Myc protein (UniProt: P01106) as originally stated in the manuscript. The PDB annotation as a “c-Myc DNA-binding protein complex” unfortunately led to a misinterpretation during structural selection. The authors acknowledge that the structure used in docking was not a crystallographic structure of c-Myc. Therefore, the docking results and interaction analyses described as “MYC–ligand” interactions are structurally attributable to RBMS1 rather than c-Myc. Any conclusions regarding direct protein–ligand interactions at the c-Myc protein interface are consequently not supported by the selected structure. The publisher hereby retracts the manuscript.