Cancer ranks among the primary contributors to global mortality. In 2022, the global incidence of new cancer cases reached about 20 million, while the number of cancer-related fatalities reached 9.7 million. In Saudi Arabia, there were 13,399 deaths caused by cancer and 28,113 newly diagnosed cases of cancer. Drug repurposing is a drug discovery strategy that has gained special attention and implementation to enhance the process of drug development due to its time- and money-saving effect. It involves repositioning existing medications to new clinical applications. Cancer treatment is a therapeutic area where drug repurposing has shown the most prominent impact. This review presents a compilation of medications that have been repurposed for the treatment of various types of cancers. It describes the initial therapeutic and pharmacological classes of the repurposed drugs and their new applications and mechanisms of action in cancer treatment. The review reports on drugs from various pharmacological classes that have been successfully repurposed for cancer treatment, including approved ones and those in clinical trials and preclinical development. It stratifies drugs based on their anticancer repurpose as multi-type, type-specific, and mechanism-directed, and according to their pharmacological classes. The review also reflects on the future potential that drug repurposing has in the clinical development of novel anticancer therapies.

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.

Cancer ranks among the primary contributors to global mortality. In 2022, the global incidence of new cancer cases reached about 20 million, while the number of cancer-related fatalities reached 9.7 million. Exclusively in Saudi Arabia, there are 13,399 deaths caused by cancer and 28,113 newly diagnosed cases of cancer. Drug repurposing is a drug discovery strategy that gained special attention and implementation to enhance the process of drug development due to its time and money saving effect. It involves repositioning existing medications to new clinical applications. Cancer treatment is one of the most therapeutic areas where drug repurposing has shown prominent impact. This review presents a compilation of medications that have been repurposed for the treatment of various types of cancers. It describes the initial therapeutic and pharmacological classes of the repurposed drugs and their new applications and mechanism of action in cancer treatment. The review reports on drugs from various pharmacological classes that have been successfully repurposed for cancer treatment including approved ones and those in clinical trials and preclinical development. It stratifies drugs based on their anticancer repurpose as multi-type, type-specific, and mechanism directed and according to their pharmacological classes. The review also reflects on the future potential that drug repurposing has in the clinical development of novel anticancer therapies.

Background/Objectives: Neutrophil cells’ lysis forms the extracellular traps (NETs) to counter the foreign body during insults to the body. Peptidyl arginine deiminase (PAD) participates in this process and is then released into the extracellular fluid with the lysed cell components. In some diseases, patients with abnormal function of PADs, especially PAD 4, tend to form autoantibodies against the abnormal citrullinated proteins that are the result of PAD activity on arginine side chains. Those antibodies, which are highly distinct in RA, are distinctly anti-citrullinated protein antibodies (ACPA). This study used an in-silico drug repurposing approach of FDA-approved medications to identify potential alternative medications that can inhibit this process and address solutions to the current limitations of existing therapies. Methods: We utilized Maestro Schrödinger as a computational tool for preparing and docking simulations on the PAD 4 enzyme crystal structure that is retrieved from RCSB Protein Data Bank (PDB ID: 4X8G) while the docked FDA-approved medications are obtained from the Zinc 15 database. The protein was bound to GSK 199—an investigational compound—as a positive control for the docked molecules. Preparation of the protein was performed by Schrödinger Protein Preparation Wizard tool. Binding pocket determination was performed by Glide software (Schrödinger Release 2021–3:Schrödinger, LLC., New York, NY, USA, 2021). and validation of molecular docking was carried out through the redocking of GSK 199 and superimposition. After that, standard and induced fit docking were performed. Results/Conclusions: Among the four obtained hits Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol, which showed the highest XP scores providing favorable binding interactions. The induced-fit docking (IFD) results displayed the strong binding affinities of Ioversol, Pemetrexed, Leucovorin, Chlordiazepoxide in the order IFD values −11.617, −10.599, −10.521, −9.988, respectively. This research investigates Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol as potential repurposing agents in the treatment of rheumatoid arthritis (RA) as they are identified as PAD4 inhibitors.