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Drug Repurposing: Emerging Approaches to Drug Discovery

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 18605

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Dr. Sona Vasudevan

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Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA
Interests: protein structures; protein-ligand interactions; drug-repurposing; systems medicine; network medicine; bioinformatics; data science
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Dear Colleagues,

Drug purposing, a methodology for identifying new therapeutic uses for existing drugs, has proven to be a highly efficient and effective strategy, saving time and cost as opposed to the lengthy, expensive road of traditional drug discovery. Over the last few decades, drug repurposing has helped mitigate failures in drug discovery. For example, the drug Sunitinib approved for use in kidney cancer was successful in treating a rare form of leukemia, opening wider avenues for the role of drug repurposing. The COVID-19 pandemic has further rekindled the development of new indications for old drugs by embracing drug repurposing through the lens of a systems and network medicine approach. This approach involves looking at perturbations of a drug to a network of genes rather than a drug docked to a single protein. In addition, artificial intelligence and machine learning approaches are playing a pivotal role in accelerating drug discovery by identifying repurposed leads based on big data sources. The focus of this Special Issue is to feature articles that apply drug repurposing to unravel new breakthroughs in drug discovery.

Dr. Sona Vasudevan
Guest Editor

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Keywords

repurposed drugs
network medicine
systems medicine
drug design
therapeutic strategies
drug repurposing in the era of artificial intelligence
drug repositioning
machine learning

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Drug Repurposing: Emerging Approaches to Drug Discovery (2nd Edition) in International Journal of Molecular Sciences

Published Papers (9 papers)

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Research

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16 pages, 2141 KiB

Open AccessArticle

Exploring Nepicastat Activity: Beyond DβH

by Rafal Jas, Marta Bauer, Błażej Grodner, Weronika Kończak, Karolina Frączek, Anna K. Laskowska, Małgorzata Milczarek, Wojciech Kamysz and Patrycja Kleczkowska

Int. J. Mol. Sci. 2025, 26(9), 4356; https://doi.org/10.3390/ijms26094356 - 3 May 2025

Viewed by 201

Abstract

Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor of DβH, nepicastat, particularly in the aspect of cocaine-seeking behavior. Hence, the objective of this study was to verify whether or not nepicastat reproduces disulfiram activity in pain reduction. Moreover, determination of its likely biological effects resulting from interactions with targets other than DβH has been given, in particular acetylcholinesterase. As was found, nepicastat was characterized by the absence of desired antinociceptive activity, though its co-administration with morphine resulted in a dose- and time-dependent enhancement of morphine-induced analgesic effect and attenuation of tolerance. Similarly, nepicastat was found to manifest antimicrobial potency against selected bacterial strains, although the effect was found to be weak. Intriguingly, this compound interacted with acetylcholinesterase through inhibition of its activity. These results clearly indicate nepicastat as a potent molecule that exhibits various biological effects. This, in turn, suggests its possible application in pathological conditions that still require effective treatment. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

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21 pages, 8928 KiB

Open AccessArticle

A Potential Use of Vidarabine: Alleviation of Functional Constipation Through Modulation of the Adenosine A2A Receptor-MLC Signaling Pathway and the Gut Microbiota

by Xiaoyu Gao, Kaifeng Guo, Shuangfeng Liu, Weixing Yang, Jun Sheng, Yang Tian, Lei Peng and Yan Zhao

Int. J. Mol. Sci. 2024, 25(23), 12810; https://doi.org/10.3390/ijms252312810 - 28 Nov 2024

Viewed by 1109

Abstract

Vidarabine (VID) is an antiviral medication that is commonly utilized to treat conditions such as hand, foot, and mouth disease and herpes. Constipation is a prevalent complication of these diseases. Could VID treat these diseases by influencing defecation behavior? To date, no studies have been conducted on the potential of VID to relieve constipation. Therefore, a systematic investigation was conducted into the laxative effects and mechanisms of VID using loperamide-induced functional constipated mice. The findings indicate that the oral administration of VID promoted gastrointestinal peristalsis, improved fecal properties, facilitated defecation, and demonstrated a significant laxative effect on functional constipated mice. It has been demonstrated that VID may increase the water content of feces by regulating the expression of aquaporins (AQP3, AQP4, and AQP8) in the colon and promote intestinal motility by regulating the expression of neurotransmitters (AChE and VIP) and the adenosine A2A receptor–myosin light chain (A2AR-MLC) signaling pathway in constipated mice. Concurrently, VID may also reduce colonic inflammation in constipated mice, reinforce the gut barrier function, and alter the composition and structure of the gut microbial community. Some microbial taxa, including Firmicutes and Lactobacillus, were found to be associated with the alleviation of constipation, while other taxa, including Bacteroidetes, Proteobacteria, Muribaculaceae, Muribaculum, norank__f__Desulfovibrionaceae, and Parasutterella, were found to be associated with constipation. These results indicate that the gut microbiota may play a significant role in the alleviation of constipation by VID. These findings confirm the efficacy of VID in a constipated animal model, which justifies further investigation into its potential clinical applications. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

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14 pages, 3548 KiB

Open AccessArticle

Metabolic Flux Analysis of Xanthomonas oryzae Treated with Bismerthiazol Revealed Glutathione Oxidoreductase in Glutathione Metabolism Serves as an Effective Target

by Hai-Long Yu, Xiao-Long Liang, Zhen-Yang Ge, Zhi Zhang, Yao Ruan, Hao Tang and Qing-Ye Zhang

Int. J. Mol. Sci. 2024, 25(22), 12236; https://doi.org/10.3390/ijms252212236 - 14 Nov 2024

Viewed by 1108

Abstract

Bacterial blight (BB) of rice caused by Xanthomonas oryzae pathovar oryzae (Xoo) is a serious global rice disease. Due to increasing bactericide resistance, developing new inhibitors is urgent. Drug repositioning offers a potential strategy to address this issue. In this study, we integrated transcriptional data into a genome-scale metabolic model (GSMM) to screen novel anti-Xoo targets. Two RNA-seq datasets (before and after bismerthiazol treatment) were used to constrain the GSMM and simulate metabolic processes. Metabolic fluxes were calculated using parsimonious flux balance analysis (pFBA) identifying reactions with significant changes for target screening. Glutathione oxidoreductase (GSR) was selected as a potential anti-Xoo target and validated through antibacterial experiments. Virtual screening based on the target identified DB12411 as a lead compound with the potential for new antibacterial agents. This approach demonstrates that integrating metabolic networks and transcriptional data can aid in both understanding antibacterial mechanisms and discovering novel drug targets. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

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15 pages, 2906 KiB

Open AccessArticle

Potential for Drug Repositioning of Midazolam as an Inhibitor of Inflammatory Bone Resorption

by Hiroko Harigaya, Risako Chiba-Ohkuma, Takeo Karakida, Ryuji Yamamoto, Keiko Fujii-Abe, Hiroshi Kawahara and Yasuo Yamakoshi

Int. J. Mol. Sci. 2024, 25(14), 7651; https://doi.org/10.3390/ijms25147651 - 12 Jul 2024

Cited by 2 | Viewed by 1411

Abstract

Drug repositioning is a method for exploring new effects of existing drugs, the safety and pharmacokinetics of which have been confirmed in humans. Here, we demonstrate the potential drug repositioning of midazolam (MDZ), which is used for intravenous sedation, as an inhibitor of inflammatory bone resorption. We cultured a mouse macrophage-like cell line with or without MDZ and evaluated its effects on the induction of differentiation of these cells into osteoclasts. For in vivo investigations, we administered lipopolysaccharide (LPS) together with MDZ (LPS+MDZ) to the parietal region of mice and evaluated the results based on the percentage of bone resorption and calvaria volume. Furthermore, we examined the effects of MDZ on the production of reactive oxygen species (ROS) in cells and on its signaling pathway. MDZ inhibited osteoclast differentiation and bone resorption activity. In animal studies, the LPS+MDZ group showed a decreasing trend associated with the rate of bone resorption. In addition, the bone matrix volume in the LPS+MDZ group was slightly higher than in the LPS only group. MDZ inhibited osteoclast differentiation by decreasing ROS production and thereby negatively regulating the p38 mitogen-activated protein kinase pathway. Thus, we propose that MDZ could potentially be used for treating inflammatory bone resorption, for example, in periodontal disease. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

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21 pages, 2484 KiB

Open AccessArticle

Inter-Species Pharmacokinetic Modeling and Scaling for Drug Repurposing of Pyronaridine and Artesunate

by Dong Wook Kang, Ju Hee Kim, Kyung Min Kim, Seok-jin Cho, Go-Wun Choi and Hea-Young Cho

Int. J. Mol. Sci. 2024, 25(13), 6998; https://doi.org/10.3390/ijms25136998 - 26 Jun 2024

Cited by 1 | Viewed by 3458

Abstract

Even though several new targets (mostly viral infection) for drug repurposing of pyronaridine and artesunate have recently emerged in vitro and in vivo, inter-species pharmacokinetic (PK) data that can extend nonclinical efficacy to humans has not been reported over 30 years of usage. Since extrapolation of animal PK data to those of humans is essential to predict clinical outcomes for drug repurposing, this study aimed to investigate inter-species PK differences in three animal species (hamster, rat, and dog) and to support clinical translation of a fixed-dose combination of pyronaridine and artesunate. PK parameters (e.g., steady-state volume of distribution (V_ss), clearance (CL), area under the concentration-time curve (AUC), mean residence time (MRT), etc.) of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) were determined by non-compartmental analysis. In addition, one- or two-compartment PK modeling was performed to support inter-species scaling. The PK models appropriately described the blood concentrations of pyronaridine, artesunate, and dihydroartemisinin in all animal species, and the estimated PK parameters in three species were integrated for inter-species allometric scaling to predict human PKs. The simple allometric equation (Y = a × W^b) well explained the relationship between PK parameters and the actual body weight of animal species. The results from the study could be used as a basis for drug repurposing and support determining the effective dosage regimen for new indications based on in vitro/in vivo efficacy data and predicted human PKs in initial clinical trials. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

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28 pages, 6252 KiB

Open AccessArticle

Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition

by Sergio Ramos, Alba Vicente-Blázquez, Marta López-Rubio, Laura Gallego-Yerga, Raquel Álvarez and Rafael Peláez

Int. J. Mol. Sci. 2023, 24(24), 17474; https://doi.org/10.3390/ijms242417474 - 14 Dec 2023

Viewed by 1786

Abstract

Antimitotic agents are one of the more successful types of anticancer drugs, but they suffer from toxicity and resistance. The application of approved drugs to new indications (i.e., drug repurposing) is a promising strategy for the development of new drugs. It relies on finding pattern similarities: drug effects to other drugs or conditions, similar toxicities, or structural similarity. Here, we recursively searched a database of approved drugs for structural similarity to several antimitotic agents binding to a specific site of tubulin, with the expectation of finding structures that could fit in it. These searches repeatedly retrieved frentizole, an approved nontoxic anti-inflammatory drug, thus indicating that it might behave as an antimitotic drug devoid of the undesired toxic effects. We also show that the usual repurposing approach to searching for targets of frentizole failed in most cases to find such a relationship. We synthesized frentizole and a series of analogs to assay them as antimitotic agents and found antiproliferative activity against HeLa tumor cells, inhibition of microtubule formation within cells, and arrest at the G₂/M phases of the cell cycle, phenotypes that agree with binding to tubulin as the mechanism of action. The docking studies suggest binding at the colchicine site in different modes. These results support the repurposing of frentizole for cancer treatment, especially for glioblastoma. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

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18 pages, 5439 KiB

Open AccessArticle

Identification of CDK1, PBK, and CHEK1 as an Oncogenic Signature in Glioblastoma: A Bioinformatics Approach to Repurpose Dapagliflozin as a Therapeutic Agent

by Harold A. Chinyama, Li Wei, Ntlotlang Mokgautsi, Bashir Lawal, Alexander T. H. Wu and Hsu-Shan Huang

Int. J. Mol. Sci. 2023, 24(22), 16396; https://doi.org/10.3390/ijms242216396 - 16 Nov 2023

Cited by 5 | Viewed by 2774

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells’ presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle’s main regulatory proteins. Herein, we identified and validated the biomarker and predictive properties of a chemoradio-resistant oncogenic signature in GBM comprising CDK1, PBK, and CHEK1 through our comprehensive in silico analysis. We found that CDK1/PBK/CHEK1 overexpression drives the cell cycle, subsequently promoting GBM tumor progression. In addition, our Kaplan–Meier survival estimates validated the poor patient survival associated with an overexpression of these genes in GBM. We used in silico molecular docking to analyze and validate our objective to repurpose Dapagliflozin against CDK1/PBK/CHEK1. Our results showed that Dapagliflozin forms putative conventional hydrogen bonds with CDK1, PBK, and CHEK1 and arrests the cell cycle with the lowest energies as Abemaciclib. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

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10 pages, 250 KiB

Open AccessCommunication

Advancements in Drug Repurposing: Examples in Psychiatric Medications

by Ryo Okuyama

Int. J. Mol. Sci. 2023, 24(13), 11000; https://doi.org/10.3390/ijms241311000 - 1 Jul 2023

Cited by 8 | Viewed by 3537

Abstract

Because there are a limited number of animal models for psychiatric diseases that can be extrapolated to humans, drug repurposing has been actively pursued. This study was aimed at uncovering recent trends in drug repurposing approaches and new technologies that can predict efficacy on humans based on animal models used in psychiatric drug development. Psychiatric drugs that were approved by the FDA between 2002 and 2022 were listed, and the method of how the drug repurposing has been applied was analyzed. Drug repurposing has been increasingly applied to recently approved psychiatric drugs. The development concepts of psychiatric drugs that have been developed through drug repurposing over the past 20 years were found to be divided into six categories: new application exploration, reduction of side effects, improvement of symptom control, improvement of medication compliance, enhancement of drug efficacy, and reduction of drug–drug interactions. All repurposed drugs approved before 2016 used either prodrugs or active metabolites, while all drugs approved in 2021 and beyond used fixed-dose combinations with sophisticated ideas. SmartCube^®, which uses artificial intelligence to predict human drug efficacy from animal phenotypes, was developed and produced novel drugs that show clinical efficacy. Well-designed drug repurposing approaches and new technologies for predicting human drug efficacy based off of animal models would contribute to novel psychiatric drug development. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

Review

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17 pages, 733 KiB

Open AccessReview

Bimekizumab in the Treatment of Axial Spondyloarthritis and Psoriatic Arthritis: A New Kid on the Block

by Julie Sarrand, Laurie Baglione, Charlotte Bouvy and Muhammad Soyfoo

Int. J. Mol. Sci. 2025, 26(5), 2315; https://doi.org/10.3390/ijms26052315 - 5 Mar 2025

Viewed by 1101

Abstract

The interleukin (IL)-17 family encompasses six structurally related pro-inflammatory cystine knot proteins, designated as IL-17A to IL-17F. Over the last decades, evidence has pointed to its role as a critical player in the development of inflammatory diseases such as psoriasis (PsO), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA). More specifically, IL-17A and IL-17F are overexpressed in the skin and synovial tissues of patients with these diseases, and recent studies suggest their involvement in promoting inflammation and tissue damage in axSpA and PsA. Bimekizumab is a monoclonal antibody targeting both IL-17A and IL-17F, playing an important role in the treatment of these diseases. This review details the implications of bimekizumab in the therapeutic armamentarium of axSpA and PsA. Full article

(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)

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