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Molecular Insights on Drug Discovery, Design, and Treatment

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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 September 2025) | Viewed by 6760

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Special Issue Editor

Prof. Dr. Chih Kang Chiang

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Guest Editor

College of Medicine, National Taiwan University, Taipei, Taiwan
Interests: nephrology; food safety and toxicology

Special Issue Information

Dear Colleagues,

In the context of today's growing global health challenges, the need for rapid development of effective and safe therapeutics for a wide range of diseases is stronger than ever. Recent insights into drug discovery, design, and treatment are providing new ideas and approaches, particularly in the following key areas:

Drug development strategy;
Identification of new drug targets;
Drug-protein interaction;
Multidisciplinary collaboration.

Drug discovery and development needs to integrate a knowledge of pharmacology, toxicology, molecular biology and other disciplines and promote the synergy between scientific research and industrial activities to find new drugs and treatments in cancer, cardiovascular diseases, neurological diseases, metabolic diseases and microbial infections. By incorporating the latest insights in drug discovery, design, and treatment, we hope to drive innovation and collaboration among the scientific community in regard to drug development, leading to safer and more effective treatment options.

Please note that papers published in the International Journal of Molecular Sciences are encouraged to include results at the molecular level. Both original research articles and reviews on these topics are welcome.

Prof. Dr. Chih Kang Chiang
Guest Editor

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Keywords

antibacterial drugs
antiviral drugs
antioxidant drugs
anti-inflammatory drugs
antibiotics
anticancer drugs
drug discovery
drug development
drug design
drug delivery
drug carriers
nanoparticles
molecular modeling
molecular mechanisms
crystallography
pharmacokinetics
molecular activity
inhibitors and antagonists

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Published Papers (6 papers)

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Research

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27 pages, 14075 KB

Open AccessArticle

Mentha rotundifolia, a Source of Amoebicidal Agents Against Naegleria fowleri

by Meriam Ben Youssef, Javier Chao-Pellicer, Eduardo Hernández-Álvarez, Amani Omrani, Ines Sifaoui, Hichem Sebai, Isabel L. Bazzocchi, José E. Piñero, Ignacio A. Jiménez and Jacob Lorenzo-Morales

Int. J. Mol. Sci. 2025, 26(18), 9048; https://doi.org/10.3390/ijms26189048 - 17 Sep 2025

Viewed by 264

Abstract

Current therapies for Primary Amoebic Meningoencephalitis (PAM) present several limitations; consequently, there is an urgent need to develop new therapeutic agents. In this regard, we undertook bioassay-guided isolation of Mentha rotundifolia leaves which allowed the identification of ursolic acid (1) as the main bioactive metabolite against two ATCC strains of Naegleria fowleri (ATCC^® 30808^TM and ATCC^® 30215^TM). Moreover, ten ursolic acid derivatives (2–11) were synthesized through esterification and nucleophilic substitution to obtain halo or amino ester derivatives. Among these derivatives, compound 7 exhibited the highest activity against the N. fowleri ATCC^® 30808^TM strain with an IC₅₀ value of 28.66 µM, whereas compound 10 showed the top activity against the N. fowleri ATCC^® 30215^TM strain with an IC₅₀ of 7.61 µM, surpassing the efficacy of the reference drug, miltefosine. Both compounds, 7 and 10, showed a good selectivity index and hence low toxicity in vitro. Structure–activity relationship studies revealed that the type of acylating agent played a crucial role in the activity. Furthermore, both compounds induced autophagy and apoptosis-like processes in both treated N. fowleri strains. These results highlight the potential of ursolic acid-related triterpenoids as drug scaffolds and identify M. rotundifolia as a promising natural source of amoebicidal agents against PAM. Full article

(This article belongs to the Special Issue Molecular Insights on Drug Discovery, Design, and Treatment)

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26 pages, 3708 KB

Open AccessArticle

The Combination Empagliflozin/Metformin Attenuates the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease in a Diet-Induced Experimental Rat Model

by Oscar René Zambrano-Vásquez, Fernando Cortes-Camacho, Juan Carlos Cabrera-Angeles, Ana Lilia Hernández-Alba, Fernando Enrique García-Arroyo, Jorge Ismael Castañeda-Sánchez, Elena Aréchaga-Ocampo, Omar Emiliano Aparicio-Trejo, Leonardo Del Valle-Mondragón, Constanza Estefanía Martínez-Olivares, Rogelio Hernández-Pando, Laura Gabriela Sánchez-Lozada and Horacio Osorio-Alonso

Int. J. Mol. Sci. 2025, 26(18), 9010; https://doi.org/10.3390/ijms26189010 - 16 Sep 2025

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses several cardiometabolic risk factors (obesity, insulin resistance, diabetes, and dyslipidemia), in addition to hepatic steatosis. Therefore, treatment is often challenging and frequently involves polypharmacy. This study investigated whether the combination of empagliflozin/metformin improves MASLD disease outcomes in an experimental model of metabolic syndrome (MS). To evaluate the efficacy of the empagliflozin/metformin (12.5/850 mg/kg/day/30 days) combination, male Wistar rats (200–220 g) were fed a Western-type diet and sugary drink to induce MS. Biochemical parameters, markers of liver damage, oxidative stress, and histopathological analysis were assessed. Also, the expression of transcription factors associated with carbohydrate and lipid metabolism and the modulation of oxidative stress were assessed. The analyses were performed with the combination and with the drugs independently. The combination empagliflozin/metformin decreased body weight, plasma triglycerides, and total cholesterol levels, while improving fasting blood glucose, oral glucose tolerance test, and plasma HDL-cholesterol levels. Additionally, it prevented hepatic hypertrophy, liver damage at both biochemical and histological levels, and intrahepatic lipid accumulation. The combination also demonstrated a significantly greater effect in improving mitochondrial function and reducing oxidative stress by modulating the Nrf2-mediated pathway. The empagliflozin/metformin combination therapy mitigates MASLD progression, likely by improving liver and mitochondrial function, and attenuating oxidative stress. Notably, co-therapy shows greater beneficial effects than single treatments. This protective effect appears to involve modulation of key transcription factors regulating lipid and carbohydrate metabolism, as well as influencing endogenous antioxidant defenses. Full article

(This article belongs to the Special Issue Molecular Insights on Drug Discovery, Design, and Treatment)

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18 pages, 2545 KB

Open AccessArticle

New Derivatives of 2-(Cyclohexylamino)thiazol-4(5H)-one as Strong Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1: Synthesis, Antiproliferative and Redox-Modulating Activity

by Szymon Baumgart, Daria Kupczyk, Anita Płazińska, Oliwia Koszła, Przemysław Sołek, Aneta Archała, Wojciech Płaziński and Renata Studzińska

Int. J. Mol. Sci. 2025, 26(18), 8972; https://doi.org/10.3390/ijms26188972 - 15 Sep 2025

Viewed by 253

Abstract

In the present study, we synthesized nine new derivatives of 2-(cyclohexylamino)thiazol-4(5H)-one and evaluated their inhibitory activity against 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1 and 11β-HSD2), an enzyme responsible for the progression of metabolic disorders and cancers. All obtained derivatives showed inhibitory potential against 11β-HSD1, and four of them highly inhibited 11β-HSD1 activity with IC₅₀ values in the low micromolar range. The most active compound, 3h with IC₅₀ = 0.04 µM, became a more potent and selective inhibitor than carbenoxolone. In addition to inhibition of 11β-HSD1, we investigated the antitumor potential and effects on intracellular redox homeostasis of all newly synthesized compounds on five cancer cell lines, namely human colon cancer (Caco-2), human pancreatic cancer (PANC-1), human glioma (U-118 MG), human breast cancer (MDA-MB-231), and skin melanoma (SK-MEL-30) and on healthy fibroblasts derived from the skin of a male neonate (BJ). Among the derivatives, all tested compounds were found to cause a decrease in cell viability for the MDA-MB-231 and Caco-2 lines and for compounds 3b–3i for SK-MEL-30. The redox-modulating activity was assessed by measuring the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reduced glutathione (GSH) using the same panel of cancer lines and normal cells. This study showed an increase in ROS levels for SK-MEL-30, Caco-2, and MDA-MB-231 lines, while in the case of GSH levels, its reduction was observed in most experimental sets. The presented data suggest that the tested compounds are promising therapeutic agents with dual action because they offer the possibility of simultaneous regulation of metabolic disorders by inhibiting 11β-HSD1 and play a key role in anticancer therapy, which makes them prospective candidates for further clinical studies. Full article

(This article belongs to the Special Issue Molecular Insights on Drug Discovery, Design, and Treatment)

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15 pages, 289 KB

Open AccessArticle

Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease

by Francesca Tavano, Orazio Palmieri, Maria Latiano, Domenica Gioffreda, Tiziana Latiano, Maria Guerra, Giuseppina Martino, Maria Rosa Valvano, Fabrizio Bossa, Francesco Perri and Anna Latiano

Int. J. Mol. Sci. 2025, 26(16), 7860; https://doi.org/10.3390/ijms26167860 - 14 Aug 2025

Viewed by 651

Abstract

Thiopurines are employed in inflammatory bowel diseases (IBDs; Crohn’s disease, CD; ulcerative colitis, UC) to induce remission, prevent relapse, and reduce the steroid dosage, although they can sometimes be ineffective and present side effects. Genetic variations in the TPMT and NUDT15 genes are well recognized to influence the therapeutic response, despite notable regional differences in their frequencies across various ethnic populations. Herein, the risk haplotypes TPMT*3A, *3B, *3C, and the variant NUDT15*3 were examined in a retrospective cohort of 383 Italian IBD patients who received azathioprine or 6-mercaptopurine. TPMT and NUDT15 genotyping was performed by Sanger sequencing and TaqMan allelic discrimination, respectively. Allelic and genotype frequencies and genotype–phenotype correlations in non-responder and intolerant patients were assessed in comparison to responders. In total, 17% of patients did not respond to treatment, while 20% experienced adverse events, with leukopenia found in 13% of patients. TPMT haplotypes were found in 3.1% of patients, and 1.6% had the NUDT15*3 variant. CD patients with leukopenia had a higher frequency of the TPMT risk haplotype (40% vs. 4%, p = 0.024). Although additional validation through larger prospective studies or meta-analyses is needed, our findings support the importance of TPMT gene-variant assessment for forecasting azathioprine-related leukopenia in Italian IBD patients. Full article

(This article belongs to the Special Issue Molecular Insights on Drug Discovery, Design, and Treatment)

Review

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20 pages, 2563 KB

Open AccessReview

Chronic Antibody-Mediated Rejection and Plasma Cell ER Stress: Opportunities and Challenges with Calcineurin Inhibitors

by Ching-Yi Tsai, Chih-Yuan Lee, Jia-Huang Chen and Chih-Kang Chiang

Int. J. Mol. Sci. 2025, 26(6), 2711; https://doi.org/10.3390/ijms26062711 - 18 Mar 2025

Cited by 1 | Viewed by 2053

Abstract

Chronic alloantibody-mediated rejection (cAMR) remains a major challenge in transplant immunology, with no FDA-approved targeted therapies currently available. Despite advancements in cellular immunosuppression, effective strategies to mitigate alloantibody-mediated rejection are still lacking. This review provides a comprehensive overview of transplant rejection with a particular focus on the pathophysiology and therapeutic landscape of cAMR. We highlight the role of plasma cell-driven alloantibody production and its susceptibility to endoplasmic reticulum (ER) stress, a pathway with potential for therapeutic intervention. Special attention is given to calcineurin inhibitors (CNIs), which, beyond their well-established T-cell inhibitory effects, exhibit differential impacts on ER stress and plasma cell viability. By delineating the mechanistic differences between cyclosporine and tacrolimus in regulating ER stress responses, we propose potential therapeutic implications for optimizing cAMR management. This review underscores the need for innovative strategies targeting plasma cell biology to improve long-term transplant outcomes. Full article

(This article belongs to the Special Issue Molecular Insights on Drug Discovery, Design, and Treatment)

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16 pages, 783 KB

Open AccessReview

Chronic Kidney Disease and Osteoarthritis: Current Understanding and Future Research Directions

by Rong-Sen Yang, Ding-Cheng Chan, Yao-Pang Chung and Shing-Hwa Liu

Int. J. Mol. Sci. 2025, 26(4), 1567; https://doi.org/10.3390/ijms26041567 - 13 Feb 2025

Cited by 1 | Viewed by 2409

Abstract

Chronic kidney disease (CKD) is a significant public health concern. Osteoarthritis (OA), a common form of arthritis, has been shown to have a dramatically increased prevalence, particularly among individuals aged 40–50 and older, in the presence of CKD. Furthermore, CKD may exacerbate the progression and impact of OA. A survey study revealed that 53.9% of CKD patients undergoing long-term hemodialysis were diagnosed with OA. These findings underscore the potential association between CKD and OA. Uremic toxins, such as indoxyl sulfate, p-cresyl sulfate, transforming growth factor-β, and advanced glycation end-products, are regarded as potential risk factors in various CKD-related conditions, affecting bone and joint metabolism. However, whether these factors serve as a bridging mechanism between CKD and OA comorbidities, as well as their detailed roles in this context, remains unclear. Addressing the progression of OA in CKD patients and identifying effective treatment and prevention strategies is an urgent challenge that warrants immediate attention. This review focuses on describing and discussing the molecular pathological mechanisms underlying CKD-associated OA and the possible therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Insights on Drug Discovery, Design, and Treatment)

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