Background/Objectives: Helicobacter pylori infects approximately half of the global population, causing chronic gastritis, peptic ulcers, and gastric cancer, a leading cause of cancer mortality. While current therapies face challenges from rising antibiotic resistance, particularly to clarithromycin, alongside treatment complexity and costs, the World Health Organization has prioritized the development of new antibiotics to combat this high-risk pathogen. In this study, we employed computer-aided drug design (CADD) methodologies, including molecular docking, Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) analysis, molecular dynamics (MD) simulations, and Density Functional Theory (DFT) calculations, to explore the potential repurposing of FDA-approved agents as inhibitors of Helicobacter pylori shikimate kinase (HpSK). Methods: Using the Glide module, the HTVS method was initially applied to screen 1615 FDA-approved agents followed by extra-precision (XP) docking for the obtained 111 hits. The obtained XP scores were used to confine the results to those hits with a score above the reference ligand, shikimate, score. This yielded 31 final hits with an XP score above −5.867. MM-GBSA calculations were performed on these top candidates and the reference ligand to refine the analysis and compounds’ prioritization. Results: The 31 compounds displayed binding free energy (ΔG_bind) values ranging from 3.61 to −55.92 kcal/mol, with shikimate exhibiting a ΔG_bind of −34.24 kcal/mol and 10 hits having a lower ΔG_bind value. Out of these ten, three drugs—Dolutegravir, Cangrelor, and Isavuconazonium—were selected for further analysis based on their drug-like properties. Robust and stable binding profiles for both Isavuconazonium and Cangrelor were verified via molecular dynamics simulation. Additionally, Density Functional Theory (DFT) analysis was conducted, and the Highest Occupied Molecular Orbitals (HOMOs), Lowest Unoccupied Molecular Orbitals (LUMOs), and the energy gap (HLG) between them were calculated. All three drug candidates displayed lower HLG values than shikimate, suggesting higher reactivity and more efficient electronic transitions than the reference ligand. Conclusions: These findings suggest that the identified drugs, although not optimal for direct repurposing, would serve as promising leads against Helicobacter pylori shikimate kinase. These drugs could be valuable leads for experimental assessment and further optimization, particularly with no prototype yet identified. In terms of potential for clinical repurposing, the results point to diflunisal as a promising candidate for further testing.

Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC₅₀ = 5.27 μM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC₅₀ = 1.94 μM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC₅₀ = 19.1 μM) versus COX-1 (IC₅₀ = 18.4 μM) as compared to celecoxib (5-LOX IC₅₀ = 16.7 μM, and COX-1 IC₅₀ = 5.9 μM). MTT assays revealed the IC₅₀ values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes.

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. Methods: This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation. The database, obtained from the Coconut website, was filtered according to a set of physicochemical descriptors, then was shape screened against the crystal ligand conformation. This filtered database consisting of 26,325 compounds was used for virtual screening against the GLP-1 allosteric site. Results: The results identified ten best hits with the XP score ranging from −9.6 to −7.6 and MM-GBSA scores ranging from −50.8 to −32.4 and another 58 hits from docked pose filter and a second round of XP docking and MM-GBSA calculation followed by molecular dynamics. The analysis of results identified hits from various natural products (NPs) classes, to whom attributed antidiabetic and anti-obesity effects have been previously reported. The results also pointed to β-lactam antibiotics that may be evaluated in drug repurposing studies for off-target effects. The calculated ADMET properties for those hits revealed suitable profiles for further development in terms of bioavailability and toxicity. Conclusions: The current study identified several NPs as potential GLP-1 positive allosteric modulators and revealed common structural scaffolds including peptidomimetics, lactams, coumarins, and sulfonamides with peptidomimetics being the most prominent especially in indole and coumarin cores.

The GTP cyclohydrolase 1 enzyme (GTPCH1) is the rate-limiting enzyme of the tetrahydrobiopterin (BH₄) biosynthetic pathway. Physiologically, BH₄ plays a crucial role as an essential cofactor for the production of catecholamine neurotransmitters, including epinephrine, norepinephrine and dopamine, as well as the gaseous signaling molecule, nitric oxide. Pathological levels of the cofactor have been reported in a number of disease states, such as inflammatory conditions, neuropathic pain and cancer. Targeting the GTPCH1 enzyme has great potential in the management of a number of disease pathologies associated with dysregulated BH₄ physiology. This study is an in silico investigation of the human GTPCH1 enzyme using virtual screening and molecular dynamic simulation to identify molecules that can be repurposed to therapeutically target the enzyme. A three-tier molecular docking protocol was employed in the virtual screening of a comprehensive library of over 7000 approved medications and nutraceuticals in order to identify hit compounds capable of binding to the GTPCH1 binding pocket with the highest affinity. Hit compounds were further verified by molecular dynamic simulation studies to provide a detailed insight regarding the stability and nature of the binding interaction. In this study, we identify a number of drugs and natural compounds with recognized anti-inflammatory, analgesic and cytotoxic effects, including the aminosalicylate olsalazine, the antiepileptic phenytoin catechol, and the phlorotannins phlorofucofuroeckol and eckol. Our results suggest that the therapeutic and clinical effects of hit compounds may be partially attributed to the inhibition of the GTPCH1 enzyme. Notably, this study offers an understanding of the off-target effects of a number of compounds and advocates the potential role of aminosalicylates in the regulation of BH₄ production in inflammatory disease states. It highlights an in silico drug repurposing approach to identify a potential means of safely targeting the BH₄ biosynthetic pathway using established therapeutic agents.

Background/Objectives: Proton pump inhibitors (PPIs) are amongst the most commonly prescribed classes of medication. However, inappropriate PPI use can lead to several adverse drug reactions (ADRs). Limited data exist on factors contributing to the risk of ADRs associated with PPI prescribing patterns in the Eastern Region of Saudi Arabia. This retrospective, cross-sectional study aimed to assess the prevalence and the pattern of PPI use and to identify factors contributing to the risk of ADRs. Methods: Data were collected from electronic medical records of patients at Al-Qateef Central Hospital from January 2020 to December 2021. The inclusion criteria included patients aged ≥40 years attending an outpatient medical care clinic. PPI prescribing patterns were categorized based on their dosage intensity into low-dose, medium-dose (MD), and high-dose (HD) categories. Binary and multinominal logistic regression models were used to determine the relationship between PPI prescribing patterns and use, categorized by MD or HD, and patient characteristics, adjusted for significant covariates. Results are presented as adjusted odds ratio (OR) with corresponding 95% confidence intervals (95% CI). Results: The study included 41,084 patients. The prevalence of PPI prescribing was 31%. PPI users were more frequently found to be females than males (52% vs. 50%, p = 0.013); they were also likely to be prescribed more medications (7 vs. 6, p < 0.001), but less likely to have gastritis-related diseases (34% vs. 32%, p < 0.001) compared to non-users. PPI HD users were more likely male (56% vs. 43%, p < 0.001), older (53 vs. 52 years, p < 0.001), and prescribed more medications (11.8 vs. 2.8, p < 0.001) compared to MD users. PPI usage was associated with concurrent use of antiplatelet drugs (OR = 1.08, 95% CI 1.01–1.15). An increasing number of prescribed medications was associated with HD usage (OR = 1.13, 95% CI 1.12–1.14), but negatively associated with MD usage (OR = 0.7 95% CI 0.69–0.71). Female gender was negatively associated with HD usage (OR = 0.85, 95% CI 0.79–0.91). Conclusions: Our findings indicate that 31% of the included cohort were prescribed PPI. Inappropriate PPI prescribing related to the drug’s omission is a concern as PPI non-users presented with valid indications such as gastritis. Male gender and increasing NPM were the common factors contributing to increased risk of PPI ADR. This study points to the importance of re-evaluating PPI use to ensure effective therapy with minimum risks of ADR.

The development of orally bioavailable non-peptidomimetic glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a promising therapeutic avenue for the treatment of type 2 diabetes mellitus (T2DM) and obesity. An extensive in silico approach combining structure-based drug design and ligand-based strategies together with pharmacokinetic properties and drug-likeness predictions is implemented to identify novel non-peptidic GLP-1RAs from the COCONUT and Marine Natural Products (CMNPD) libraries. More than 700,000 compounds were screened by shape-based similarity filtering in combination with precision docking against the orthosteric site of the GLP-1 receptor (PDB ID: 6X1A). The docked candidates were further assessed with the molecular mechanics MM-GBSA tool to check the binding affinities; the final list of candidates was validated by running a 500 ns long MD simulation. Twenty final hits were identified, ten from each database. The hits contained compounds with reported antidiabetic effects but with no evidence of GLP-1 agonist activity, including hits 1, 6, 7, and 10. These findings proposed a novel mechanism for these hits through GLP-1 activity and positioned the other hits as potential promising scaffolds. Among the studied compounds—especially hits 1, 5, and 9—possessed strong and stable interactions with critical amino acid residues such as TRP-203, PHE-381, and GLN-221 at the active site of the 6X1A-substrate along with favorable pharmacokinetic profiles. Moreover, the RMSF and RMSD plots further suggested the possibility of stable interactions. Specifically, hit 9 possessed the best docking score with a ΔG_bind value of −102.78 kcal/mol, surpassing even the control compound in binding affinity. The ADMET profiling also showed desirable drug-likeness and pharmacokinetic characteristics for hit 9. The pipeline of computational integration underscores the potential of non-peptidic alternatives in natural product libraries to pursue GLP-1-mediated metabolic therapy into advanced preclinical validation.