Hadil Alahdal

Lung cancer is one of the leading causes of cancer-related deaths globally, with smoking being the primary risk factor, though environmental exposures and genetic mutations also play significant roles. Lung cancer arises when abnormal lung cells grow uncontrollably, leading to over 2 million new cases and nearly 1.8 million deaths globally. Drug resistance, especially to targeted therapies, is a key challenge, as tumours often adapt and become unresponsive. Multitargeted drug design, which targets multiple pathways involved in tumour growth, offers a promising solution to overcome resistance and improve treatment efficacy. In this study, we identified several lung cancer–associated proteins: CK2, Ran–Importin β complex, HNGF, Human Survivin, CRK-II adaptor protein, AKR1B10, and tRNA dihydrouridine synthase 2, with respective PDB IDs 1JWH, 1IBR, 1SG1, 1XOX, 2DVJ, 4XZL, and 4XP7. We conducted molecular docking using DrugBank’s library, employing HTVS, SP, and XP, followed by pose processing with MM/GBSA. Our multitarget docking analysis identified Quercetin-3-O-Phosphate as the top compound, a quercetin derivative found in fruits and vegetables such as onions, apples, berries, broccoli, and citrus. The compound showed docking and MM/GBSA scores ranging from −5.835 to −11.627 Kcal/mol and −14.28 to −47.07 Kcal/mol, respectively, and the key interacting residues with their counts include 10ASP, 9LEU, 9LYS, 7ALA, 7ARG, 7TYR, 6GLN, 5ASN, 5GLU, 5ILE, and 5VAL. We also performed and analysed DFT and pharmacokinetics in detail, which supported its further evaluation as it met all the required criteria. We conducted a 5 ns WaterMap simulation, which confirmed the interactions and highlighted key hydration sites that support the complex’s stability. A 100 ns MD simulation using the TIP3P water model showed minimal deviation and fluctuations, indicating stable interactions and the trajectories used for MM/GBSA calculations, assessing binding free, which reinforced the stability of the complexes and helped rank the best candidates. All results indicate that Quercetin-3-O-Phosphate holds strong potential for lung cancer treatment, though experimental validation is needed for clinical confirmation.

Micro-RNAs (miRNAs) are recurrently dysregulated across solid and hematologic malignancies. They are most useful clinically when interpreted as state reporters of hallmark programs, including PI3K/AKT survival, p53 checkpoint loss, MYC-linked proliferation, epithelial-to-mesenchymal transition plasticity, hypoxia adaptation, and immune escape. This chapter builds a pan-cancer framework around a set of high-centrality miRNA nodes repeatedly observed in cancer biology and liquid biopsies, including miR-21, the miR-34 family, the miR-17 ~92 cluster, the let-7 family, the miR-200 family, miR-210, miR-155, and miR-221/222. Additionally, the chapter expands to include clinically relevant modules such as, miR-126 angiogenesis, miR-16/15 checkpoint for apoptosis, miR-29 epigenetic remodeling, miR-146a inflammatory tone, miR-122 metabolism, and miR-10b/miR-9 plasticity/CSC programs. These modules are translated into therapy-relevant biology across chemotherapy, targeted therapy, endocrine therapy, radiotherapy, and immunotherapy, emphasizing mechanisms of response, escape, and resistance. Finally, state modules are mapped to clinical cases from early detection, tumor characterization, prognosis, monitoring, and early resistance detection. Each section clarifies what level of evidence supports each type of claim. The chapter provides an integrated view to link modules and pathways to treatment consequences with clinical decisions. This adds to genomics results and clarifies where miRNA biomarkers are strongest, where they fail to be explained by tumor–host biology, and where validation is still required.

Acute lymphoblastic leukemia (ALL) is a clinically diverse cancer in which microRNA (miRNA)-mediated post-transcriptional regulation contributes to leukemogenesis and subtype heterogeneity. In this study, miRNA expression profiling by microarray was performed on ALL cases (B-ALL and T-ALL) and healthy controls. Data were normalized and analyzed for differential expression using false discovery rate (FDR)-adjusted p-values. Differentially expressed miRNAs were further examined using unsupervised visualization to assess overall disease-related expression patterns. To explore their biological significance, experimentally validated miRNA–target interactions were obtained using multiMiR, limited to validated databases (miRTarBase, TarBase, and miRecords) and summarized via target-burden ranking, miRNA–target network analysis, and Circos–style interaction mapping. A unique miRNA expression signature was identified in ALL. Upregulated miRNAs included miR-106a-5p, miR-106b-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-181b-5p, and miR-128-3p, while miR-127-3p, miR-139-5p, miR-433-3p, and miR-584-5p were downregulated. Validated targets concentrated on key leukemia-related genes like PTEN, BCL2L11, CDKN1A, CCND1, RB1, E2F1, and TGFBR2. KEGG pathway analysis highlighted pathways associated with leukemic cell survival and growth, including MAPK, cell cycle, autophagy, Hippo, ubiquitin-mediated proteolysis, and mTOR signaling pathways. These findings reveal a concise ALL-associated miRNA panel predominantly comprising the miR-17/20/106 family and provide a prioritized set of candidate regulatory networks for subtype-specific validation and functional follow-up studies.

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterised by the accumulation of neurotoxic substances in the brain, ultimately leading to progressive cognitive decline. The complex aetiology and involvement of multiple molecular targets in AD pathogenesis have made discovering effective therapeutic agents particularly challenging. Targeting multiple proteins simultaneously with a single therapeutic agent may offer a promising strategy to address the disease’s multifaceted nature. Methods: This study employed advanced computational methodologies to perform multitargeted molecular docking of FDA-approved drugs against four key AD-associated proteins implicated in disease progression. Among the screened compounds, Rebamipide—a drug conventionally used for treating gastrointestinal disorders—demonstrated notable binding affinities across all targets. Pharmacokinetic predictions, interaction fingerprinting, WaterMap analysis, density functional theory (DFT) calculations, and 100 ns MD simulations were performed for each protein–ligand complex to evaluate its multitarget potential. Results: Rebamipide bound effectively to the NR1 ligand-binding core, suggesting modulation of glutamatergic signalling while reducing β-secretase production and regulating neurotransmitter homeostasis through inhibiting monoamine oxidase-A. Furthermore, Rebamipide enhanced cholinergic neurotransmission by inhibiting human acetylcholinesterase, potentially improving cognitive function. Pharmacokinetic analyses confirmed favourable drug-like properties. Molecular interaction fingerprints revealed consistent hydrogen bonding, hydrophobic contacts, and π-π stacking interactions. WaterMap analysis indicated thermodynamically favourable water displacement upon binding, enhancing ligand affinity. DFT analysis of Rebamipide showed a 4.24 eV HOMO-LUMO gap, with ESP values ranging from −6.63 × 10⁻² to +6.63 × 10⁻² A.U., indicating reactive sites. TDDFT predicted strong UV absorption at 314 nm with a peak intensity of ~6500 L mol⁻¹ cm⁻¹. MD simulations over 100 ns demonstrated minimal structural deviations and stable ligand–protein complexes, reinforcing its multitarget efficacy. Conclusions: The comprehensive in silico investigation highlights Rebamipide as a promising multitargeted therapeutic candidate for Alzheimer’s disease. Its ability to modulate multiple pathogenic pathways simultaneously underscores its potential utility; however, these computational findings warrant further experimental validation to confirm its efficacy and therapeutic relevance in AD.

Background: Breast cancer remains a significant global health concern, with approximately 2.3 million diagnosed cases and 670,000 deaths annually. Current targeted therapies face challenges such as resistance and adverse side effects. This study aimed to explore natural compounds as potential multitargeted breast cancer therapeutics, focusing on Lucidin, an anthraquinone derived from Rubia cordifolia, and comparing its efficacy with Lapatinib, an FDA-approved drug. Methods: We performed multitargeted molecular docking studies on key breast cancer proteins using a natural compound library from ZINC. Comparative analyses of Lucidin and Lapatinib included molecular interaction fingerprints, pharmacokinetics, WaterMap computations (5 ns) to assess water thermodynamics and binding interactions, and Molecular Dynamics Simulations (100 ns) in water to evaluate complex stability and dynamic behaviour. Results: Lucidin demonstrated significant binding affinity and interaction potential with multiple breast cancer targets, outperforming Lapatinib in stability and binding interactions. WaterMap analysis revealed favourable hydration site energetics for Lucidin, enhancing its efficacy. The multitargeted profile of Lucidin suggests a broader therapeutic approach with potential to overcome resistance and side effects associated with Lapatinib. Conclusions: Lucidin shows promise as a novel, multitargeted anti-breast cancer agent with improved efficacy over Lapatinib. These findings provide a foundation for further in vitro and in vivo validation to develop Lucidin as a potential therapeutic option for breast cancer treatment.

Multidrug-resistant (MDR) Salmonella remains a significant global health threat. This study aimed to explore the potential of essential oil components as novel inhibitors of the Salmonella MDR efflux pumps AcrAB and AcrD. Salmonella isolates were characterized for serotype, antibiotic resistance, and efflux pump activity. Essential oil components were screened for inhibitory effects using phenotypic and genotypic methods. In silico docking and molecular dynamics simulations were conducted to investigate binding interactions and stability. Salmonella Typhimurium was the predominant serotype with high MDR rates. Efflux pump activity was prevalent. Cumin and cinnamon oils demonstrated promising inhibitory effects on these pumps. Molecular docking simulations revealed strong binding affinities of analyzed compounds to the AcrAB and AcrD binding pocket. The 2-methyl-1-(p-tolyl)propan-2-ol exhibited higher stability within the AcrAB binding pocket compared to (1S,3R,5R)-1-isopropyl-4-methylenebicyclo[3.1.0]hexan-3-ol within the AcrD binding pocket. Treatment with these oils significantly downregulated efflux pump genes (robA, acrB, mdtB, acrF, acrD, soxS, mdsB, marA). The novel approach of combining in silico and molecular dynamics simulations with precise gene expression analysis provides a valuable framework for future studies aimed at combating MDR Salmonella efflux pumps.

B-cell acute lymphoblastic leukemia (B-ALL) accounts for 85% of all childhood ALL. Malignancies exhaust T and B cells, resulting in an increased expression of immune checkpoint receptors (ICRs), such as T-cell immunoglobulin and mucin domain 3 (TIM-3). TIM-3 has been found to be dysregulated in different types of cancer. However, there is a lack of rigorous studies on the TIM-3 expression in B-ALL. The current study aimed to measure the expression of TIM-3 at the gene and protein levels and evaluate the potential of TIM-3 as a biomarker in B-ALL. A total of 28 subjects were recruited between 2021 and 2023, comprising 18 subjects diagnosed with B-ALL and 10 non-malignant healthy controls. The B-ALL patients were divided into three groups: newly diagnosed (four patients), in remission (nine patients), and relapse/refractory (five patients). The expression levels of TIM-3 were evaluated using the real-time qPCR and ELISA techniques. The results revealed that the TIM-3 expression was significantly downregulated in the malignant B-ALL patients compared to the non-malignant healthy controls in the mRNA (FC = −1.058 ± 0.3548, p = 0.0061) and protein blood serum (p = 0.0498) levels. A significant TIM-3 gene reduction was observed in the relapse/refractory cases (FC = −1.355 ± 0.4686, p = 0.0327). TIM-3 gene expression allowed for significant differentiation between patients with malignant B-ALL and non-malignant healthy controls, with an area under the curve (AUC) of 0.706. The current study addressed the potential of reduced levels of TIM-3 as a negative biomarker for B-ALL patients.

Herpesvirus entry mediator (HVEM) is a molecular switch that can modulate immune responses against cancer. The significance of HVEM as an immune checkpoint target and a potential prognostic biomarker in malignancies is still controversial. This study aims to determine whether HVEM is an immune checkpoint target with inhibitory effects on anti-tumor CD4⁺ T cell responses in vitro and whether HVEM gene expression is dysregulated in patients with acute lymphocytic leukemia (ALL). HVEM gene expression in tumor cell lines and peripheral blood mononuclear cells (PBMCs) from ALL patients and healthy controls was measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Tumor cells were left untreated (control) or were treated with an HVEM blocker before co-culturing with CD4⁺ T cells in vitro in a carboxyfluorescein succinimidyl ester (CFSE)-dependent proliferation assay. HVEM expression was upregulated in the chronic myelogenous leukemia cell line (K562) (FC = 376.3, p = 0.086) compared with normal embryonic kidney cells (Hek293). CD4⁺ T cell proliferation was significantly increased in the HVEM blocker-treated K562 cells (p = 0.0033). Significant HVEM differences were detected in ALL PBMCs compared with the controls, and these were associated with newly diagnosed ALL (p = 0.0011) and relapsed/refractory (p = 0.0051) B cell ALL (p = 0.0039) patients. A significant differentiation between malignant ALL and the controls was observed in a receiver operating characteristic (ROC) curve analysis with AUC = 0.78 ± 0.092 (p = 0.014). These results indicate that HVEM is an inhibitory molecule that may serve as a target for immunotherapy and a potential ALL biomarker.

Crohn’s disease (CD) entails intricate interactions with gut microbiome diversity, richness, and composition. The relationship between CD and gut microbiome is not clearly understood and has not been previously characterized in Saudi Arabia. We performed statistical analysis about various factors influencing CD activity and microbiota dysbiosis, including diagnosis, treatment, and its impact on their quality of life as well as high-throughput metagenomic V3-V4 16S rRNA encoding gene hypervariable region of a total of eighty patients with CD, both in its active and inactive state with healthy controls. The results were correlated with the demographic and lifestyle information, which the participants provided via a questionnaire. α-diversity measures indicated lower bacterial diversity and richness in the active and inactive CD groups compared to the control group. Greater dysbiosis was observed in the active CD patients compared to the inactive form of the disease, showed by a reduction in microbial diversity. Specific pathogenic bacteria such as Filifactor, Peptoniphilus, and Sellimonas were identified as characteristic of CD groups. In contrast, anti-inflammatory bacteria like Defluviitalea, Papillibacter, and Petroclostridium were associated with the control group. Among the various factors influencing disease activity and microbiota dysbiosis, smoking emerged as the most significant, with reduced α-diversity and richness for the smokers in all groups, and proinflammatory Fusobacteria was more present (p.05). Opposite to the control group, microbial diversity and richness were lower in CD participants of older age compared to younger ones, and male CD participants showed less diversity compared to women participants from the same groups. Our results describe the first report on the relationship between microbiota and Crohn’s disease progress in Saudi Arabia, which may provide a theoretical basis for the application of therapeutic methods to regulate gut microbes in CD.