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Drug Repurposing: Emerging Approaches to Drug Discovery (2nd Edition)
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Drug Repurposing: Emerging Approaches to Drug Discovery (2nd Edition)

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 (30 September 2025) | Viewed by 3207

Special Issue Editor

Dr. Sona Vasudevan

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug repurposing, 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 the repurposing of the drug. 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

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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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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Related Special Issue

Published Papers (3 papers)

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Research

23 pages, 6060 KB  
Article
Duloxetine, an SNRI, Targets pSTAT3 Signaling: In-Silico, RNA-Seq and In-Vitro Evidence for a Pleiotropic Mechanism of Pain Relief
by Sayed Aliul Hasan Abdi, Gohar Azhar, Xiaomin Zhang and Jeanne Y. Wei
Int. J. Mol. Sci. 2025, 26(21), 10432; https://doi.org/10.3390/ijms262110432 - 27 Oct 2025
Viewed by 745
Abstract
Chronic pain is a serious health issue, often irrationally managed by conventional analgesics. Duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI), also effective in neuropathic and musculoskeletal pain, but the molecular mechanism of its analgesic action is still unclear. Here, we examined whether Duloxetine exerts [...] Read more.
Chronic pain is a serious health issue, often irrationally managed by conventional analgesics. Duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI), also effective in neuropathic and musculoskeletal pain, but the molecular mechanism of its analgesic action is still unclear. Here, we examined whether Duloxetine exerts pleiotropic effects by directly targeting phosphorylated STAT3 (pSTAT3), a key regulator of neuroinflammation and pain sensitization. Molecular docking showed that Duloxetine binds with pSTAT3 with binding energy −5.83 kcal/mol. Ruxolitinib, a JAK/STAT inhibitor used as reference, showed binding energy of −6.19 kcal/mol. Molecular dynamics (MD) simulations confirmed stable Duloxetine–pSTAT3 complexes, while MM-PBSA free energy analysis revealed more favorable binding for Duloxetine (ΔG = −15.17 kJ·mol−1) than Ruxolitinib (ΔG = −12.98 kJ·mol−1) for pSTAT3. In-vitro analyses, Western blot showed that Duloxetine significantly reduced IL-6–induced STAT3 and pSTAT3 expression in C2C12 cells in a dose-dependent manner (6.4 and 12.8 μM, *** p < 0.0001), although Ruxolitinib produced a stronger suppression. Transcriptomic analysis revealed Duloxetine-specific enrichment of mitochondrial, oxidative phosphorylation, and synaptic pathways, distinct from the immune-suppressive influence of Ruxolitinib. RNA-seq further revealed that STAT3 transcript abundance remains constant under all treatment conditions, indicating that post-transcriptional or post-translational mechanisms, such as phosphorylation-dependent activation, may be involved rather than transcriptional modulation of STAT3 in action of Ruxolitinib and Duloxetine and the formation of novel STAT3 indicating enhanced transcript diversity. The rMATS splicing analysis confirmed dose-dependent modulation, with Duloxetine promoting mild exon skipping at 6.4 μM (IncLevel 0.90 → 0.80) and recovery at 12.8 μM (0.85 → 0.86), while Ruxolitinib induced stronger exon inclusion (0.85 → 1.00,0.94), with broader transcript suppression at 6.4 μM and 12.8 μM, respectively. These findings establish Duloxetine as a dual-action therapeutic that combines neurotransmitter reuptake inhibition with pSTAT3 suppression and isoform-level transcriptomic modulation. This pleiotropic mechanism provides a rationale for its durable analgesic effects and supports repurposing in STAT3-associated disorders. Full article
(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery (2nd Edition))
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26 pages, 5170 KB  
Article
Minocycline Treatment Improves Memory and Reduces Anxiety by Lowering Levels of Brain Amyloid Precursor Protein and Indoleamine 2,3-Dioxygenase in a Rat Model of Streptozotocin-Induced Alzheimer’s Disease
by Grzegorz Świątek, Jowita Nowakowska-Gołacka, Monika Słomińska-Wojewódzka, Wojciech Glac, Oliwia Harackiewicz, Ewelina Kurowska-Rucińska and Danuta Wrona
Int. J. Mol. Sci. 2025, 26(19), 9397; https://doi.org/10.3390/ijms26199397 - 26 Sep 2025
Viewed by 1124
Abstract
Minocycline (MINO), a classic antibiotic, may have psychotropic activity related to the modulation of the tryptophan-kynurenine pathway. In this study, we investigated the effects of MINO on (1) memory and anxiety behaviors, (2) the modulation of brain levels of amyloid precursor protein (APP) [...] Read more.
Minocycline (MINO), a classic antibiotic, may have psychotropic activity related to the modulation of the tryptophan-kynurenine pathway. In this study, we investigated the effects of MINO on (1) memory and anxiety behaviors, (2) the modulation of brain levels of amyloid precursor protein (APP) and 2,3-indoleamine dioxygenase (IDO1) levels, and (3) peripheral inflammatory markers in a streptozotocin (STZ)-induced rat model of sporadic Alzheimer’s disease (sAD). After repeated treatment with a dose of 35 mg/kg MINO for seven consecutive days, male Wistar rats with sAD showed (1) improvements in early (29 days after injection, probe test) reference memory (decreased latency to reach the platform, increased time in the critical quadrant of the Morris water maze) and anxiety disorders (increased time in the open arms of the elevated plus maze; increased exploration and entrances in the center of the white–light illuminated open field) 45–46 and 90–91 days after STZ injection; (2) reduced APP and IDO1 levels in the hippocampus and prefrontal cortex; and (3) induction of anti-inflammatory response in blood (increased TCD4+ lymphocyte number and interleukin-10 production). This suggests that MINO, due to its anti-inflammatory action, improves memory and anxiety behavior related to sAD, indicating its neuroprotective and psychotropic properties. Full article
(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery (2nd Edition))
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26 pages, 3581 KB  
Article
Differential Effects of Losartan and Finerenone on Diabetic Remodeling, Oxidative Stress and ACE Activity in the Gastrointestinal Tract of Streptozotocin-Induced Diabetic Rats
by Marisa Esteves-Monteiro, Cláudia Vitorino-Oliveira, Joana Castanheira-Moreira, Mariana Ferreira-Duarte, Patrícia Dias-Pereira, Vera Marisa Costa, Manuela Morato and Margarida Duarte-Araújo
Int. J. Mol. Sci. 2025, 26(13), 6294; https://doi.org/10.3390/ijms26136294 - 29 Jun 2025
Viewed by 1020
Abstract
Gastrointestinal (GI) complications are common in diabetes, but the role of the local renin-angiotensin-aldosterone system (RAAS) in gut remodeling remains unclear. This study examined histomorphometric alterations, oxidative stress, and systemic and tissue-specific angiotensin converting enzyme (ACE) and ACE2 activity in streptozotocin (STZ)-induced diabetic [...] Read more.
Gastrointestinal (GI) complications are common in diabetes, but the role of the local renin-angiotensin-aldosterone system (RAAS) in gut remodeling remains unclear. This study examined histomorphometric alterations, oxidative stress, and systemic and tissue-specific angiotensin converting enzyme (ACE) and ACE2 activity in streptozotocin (STZ)-induced diabetic rats. Adult male Wistar rats (n = 24) were assigned to control (CTRL), diabetic (STZ), and diabetic groups treated with losartan (STZ-LOS, 20 mg/kg/day) or finerenone (STZ-FIN, 10 mg/kg/day). After 14 days, gut samples were collected from the stomach, duodenum, jejunum, ileum, and colon for histology, glutathione measurements (GSH/GSSG), and ACE/ACE2 activity assessment. Diabetic rats exhibited increased GI wall thickness—particularly in the mucosal and muscular layers—elevated GSSG levels, and a reduced GSH/GSSG ratio. Losartan prevented these changes, whereas finerenone did not produce a significant effect. Circulating ACE and ACE2 levels were elevated, but the ACE2/ACE ratio remained unchanged. Locally, ACE activity increased across gut segments, whereas ACE2 remained stable, lowering the ACE2/ACE ratio, particularly in the duodenum and jejunum. The Z-FHL/h-HL ratio was above 1 across segments but decreased in these same regions (jejunum and duodenum). These findings highlight the protective role of losartan against diabetic GI remodeling via AT1R blockade and suggest complex, segment-specific RAAS regulation in diabetic gut pathology. Full article
(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery (2nd Edition))
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