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.

Drug repurposing, or repositioning, has emerged as a pivotal strategy in pharmaceutical research, offering a promising approach to uncover new therapeutic uses for existing drugs. While traditional de novo drug discovery typically requires 10-17 years and investments exceeding $2 billion with only 11% of Phase I candidates reaching approval, drug repurposing can reduce development timelines to 3-12 years at substantially lower costs, with approval rates reaching approximately 30% for de-risked compounds. The current review evaluates recent approaches, benefits, challenges and successful examples of drug repurposing. Relevant literature related to the advantages and obstacles associated with drug repurposing were reviewed. Additionally, the review demonstrates computational and data-driven methods, as well as traditional and novel examples of repurposed drugs across different therapeutic fields. Drug repurposing offers a faster and cost-effective approach to new therapies, particularly for critical conditions, such as rare diseases, neurodegenerative disorders and cancer. These advantages overcome the shortcomings of traditional drug development. Successful examples include the repurposing of dimethyl fumarate, chloroquine and daptomycin, which addressed a range of medical indications beyond the original drug uses. Collectively, these findings demonstrate that drug repurposing provides a viable solution for accelerating the process of drug discovery and addressing urgent medical needs. The integration of advanced computational methods and enhancing collaborative research projects would allow further expansion of treatment options and supporting timely solutions for critical and rare medical conditions.

DPP4 (Dipeptidyl-peptidase 4) a versatile protease, emerges as a prominent player in soluble and membrane-bound forms. Its heightened expression has been intimately linked to the initiation and severity of diverse autoimmune diseases, spanning rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (SSc), inflammatory bowel disease, autoimmune diabetes, and even SARS-CoV-2 infection. Operating as a co-stimulator of T cell activity, DPP4 propels T cell proliferation by binding adenosine deaminase (ADA), thereby augmenting the breakdown of adenosine—an influential inhibitor of T cell proliferation. However, the discovery of a wide range of DPP4 inhibitors has shown promise in alleviating these diseases’ signs, symptoms, and severity. The available DPP4 inhibitors have demonstrated significant effectiveness in blocking DPP4 activity. Based on the characterization of their binding mechanisms, three distinct groups of DPP4 inhibitors have been identified: saxagliptin, alogliptin, and sitagliptin, each representing a different class. Elevated levels of angiotensin-converting enzyme 2 (ACE2) expression are associated with producing various coronavirus peptidases. With its anti-inflammatory properties, Sitagliptin may assist COVID-19 patients in preventing and managing cytokine storms. This comprehensive review delves into the burgeoning realm of DPP4 inhibitors as therapeutic interventions for diverse autoimmune diseases. With a discerning focus on their efficacy, the investigation sheds light on their remarkable capacity to alleviate the burdensome signs and symptoms intricately linked to these conditions.

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.

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.