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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: 28 February 2026 | Viewed by 13651

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Special Issue Editor

Dr. Woo-kyung Kim

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Guest Editor

1. Channelopathy Research Center (CRC), Dongguk University College of Medicine, 32 Dongguk-ro, Ilsan Dong-gu, Gyeonggi-do, Goyang 10326, Republic of Korea
2. Department of Internal Medicine, Graduate School of Medicine, Dongguk University, 27 Dongguk-ro, Ilsan Dong-gu, Gyeonggi-do, Goyang 10326, Republic of Korea
Interests: allergy; atopy; inflammation; natural products; ion channels; pain; pruritus; sensory; nerve; drug discovery; mechanism

Special Issue Information

Dear Colleagues,

Introduction: The journal aims to serve as a comprehensive platform for the dissemination of cutting-edge research and advancements in the field of Drug Discovery Based on Natural Products. Focused on bridging the gap between traditional medicine and modern pharmacology, the journal welcomes contributions that explore the vast reservoirs of bioactive compounds found in nature.

Key Themes and Topics:

Identification and Characterization of Bioactive Compounds:

Exploration of novel compounds from plants, microbes, marine organisms, and other natural sources.
Methods for isolation, purification, and structural elucidation of bioactive molecules.

Pharmacological Activities and Mechanisms:

In-depth studies on the pharmacological properties of natural products.
Investigations into the mechanisms of action underlying the therapeutic potential of these compounds.

Synergies with Modern Drug Development:

Integration of natural products into drug development pipelines.
Synergies between natural and synthetic compounds for enhanced therapeutic efficacy.

Emerging Technologies in Natural Product Research:

Application of omics technologies (genomics, proteomics, metabolomics) in natural product research.
Computational approaches for the prediction of bioactivity and drug-likeness.

We invite researchers, academicians, pharmaceutical professionals, and those with an interest in drug discovery, pharmacology, and natural product research to present their original research articles, reviews, and perspectives that contribute to the understanding of natural product-based drug discovery. Manuscripts employing interdisciplinary approaches are particularly encouraged. By providing a dedicated platform for the exchange of knowledge, IJMS aims to foster collaboration and accelerate advancements in the dynamic and evolving field of Drug Discovery Based on Natural Products.

Dr. Woo-kyung Kim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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

drug discovery
bioactive compounds
pharmacological activities and mechanisms
omics technologies

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Published Papers (7 papers)

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11 pages, 2125 KB

Open AccessArticle

Regulation of T Lymphocyte Functions through Calcium Signaling Modulation by Nootkatone

by Ji Min Lee, Jintae Kim, Su Jin Park, Joo Hyun Nam, Hyun Jong Kim and Woo Kyung Kim

Int. J. Mol. Sci. 2024, 25(10), 5240; https://doi.org/10.3390/ijms25105240 - 11 May 2024

Cited by 3 | Viewed by 2099

Abstract

Recent advancements in understanding the intricate molecular mechanisms underlying immunological responses have underscored the critical involvement of ion channels in regulating calcium influx, particularly in inflammation. Nootkatone, a natural sesquiterpenoid found in Alpinia oxyphylla and various citrus species, has gained attention for its diverse pharmacological properties, including anti-inflammatory effects. This study aimed to elucidate the potential of nootkatone in modulating ion channels associated with calcium signaling, particularly CRAC, K_V1.3, and K_Ca3.1 channels, which play pivotal roles in immune cell activation and proliferation. Using electrophysiological techniques, we demonstrated the inhibitory effects of nootkatone on CRAC, K_V1.3, and K_Ca3.1 channels in HEK293T cells overexpressing respective channel proteins. Nootkatone exhibited dose-dependent inhibition of channel currents, with IC₅₀ values determined for each channel. Nootkatone treatment did not significantly affect cell viability, indicating its potential safety for therapeutic applications. Furthermore, we observed that nootkatone treatment attenuated calcium influx through activated CRAC channels and showed anti-proliferative effects, suggesting its role in regulating inflammatory T cell activation. These findings highlight the potential of nootkatone as a natural compound for modulating calcium signaling pathways by targeting related key ion channels and it holds promise as a novel therapeutic agent for inflammatory disorders. Full article

(This article belongs to the Special Issue Drug Discovery Based on Natural Products)

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13 pages, 5986 KB

Open AccessArticle

Agrimonia coreana Extract Exerts Its Therapeutic Effect through CRAC Channel Inhibition for Atopic Dermatitis Treatment

by Jintae Kim, Ji Min Lee, Su Jin Park, Yu Ran Nam, Seong Woo Choi, Joo Hyun Nam, Hyun Jong Kim and Woo Kyung Kim

Int. J. Mol. Sci. 2024, 25(16), 8894; https://doi.org/10.3390/ijms25168894 - 15 Aug 2024

Viewed by 1976

Abstract

Atopic dermatitis (AD) is a common allergic inflammatory skin condition marked by severe itching, skin lichenification, and chronic inflammation. AD results from a complex immune response, primarily driven by T lymphocytes and environmental triggers, leading to a disrupted epidermal barrier function. Traditional treatments, such as topical corticosteroids, have limitations due to long-term side effects, highlighting the need for safer alternatives. Here, we aimed to show that Agrimonia coreana extract (AC_ext) can be used in treating AD-related dermatologic symptoms. AC_ext could inhibit CRAC (Calcium Release-Activated Calcium) channel activity, reducing Orai1/CRAC currents and decreasing intracellular calcium signaling. This inhibition was further confirmed by the reduced IL-2 levels and T cell proliferation upon AC_ext treatment. In a mouse model of AD, AC_ext significantly ameliorates symptoms, improves histological parameters, and enhances skin barrier function, demonstrating its potential for treating AD. Full article

(This article belongs to the Special Issue Drug Discovery Based on Natural Products)

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19 pages, 1312 KB

Open AccessArticle

High-Throughput Screening of Five Compound Libraries for Anthelmintic Activity and Toxicity Leads to the Discovery of Two Flavonoid Compounds

by Giulio Galli, Marta Ruiz-Somacarrera, Laura González del Palacio, Estela Melcón-Fernández, Rubén González-Pérez, Carlos García-Estrada, Maria Martinez-Valladares and Rafael Balaña-Fouce

Int. J. Mol. Sci. 2025, 26(4), 1595; https://doi.org/10.3390/ijms26041595 - 13 Feb 2025

Cited by 2 | Viewed by 2445

Abstract

Gastrointestinal nematode infections (GINs) in ruminants are a major constraint to efficient livestock production worldwide. Currently, only a limited number of anthelmintic drugs are available for the control of these infections, but their widespread use in preventive deworming campaigns and the incorrect administration of the drugs are responsible for the emergence of resistance. Therefore, new anthelmintic drugs are urgently needed. However, drug discovery methods for new anthelmintics based on GINs isolated from ruminants often have low throughput. In this study, a screening of five commercial collections of chemical compounds, including one collection of anti-infective drugs, three plant-based natural product collections, and one collection from the FDA-approved Chinese Pharmacopoeia, with a total of 2228 molecules, have been carried out in a high-throughput format. In the single slot screen, 32 compounds (1.44% success rate) achieved a >70% motility inhibition rate. Of these, 10 are known anthelmintic drugs, while the remaining 22 were tested against Haemonchus contortus and a resistant strain of Teladorsagia circumcincta. Four compounds (two flavonoids, chalcone and trans-chalcone), and two anti-infectives (octenidine and tolfenpyrad), showed anthelmintic activity with EC₅₀ values below 20 µM, and were further tested for their safety against HepG2 spheroids and mouse intestinal organoids. Trans-chalcone and chalcone emerged as promising candidates for future development, showing selective indexes > 5, while tolfenpyrad and octenidine require careful evaluation due to their toxicity profiles. Full article

(This article belongs to the Special Issue Drug Discovery Based on Natural Products)

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22 pages, 5075 KB

Open AccessArticle

Evaluation of the Inhibitory Potential of Apigenin and Related Flavonoids on Various Proteins Associated with Human Diseases Using AutoDock

by Tanat Peanlikhit, Uma Aryal, James S. Welsh, Kenneth R. Shroyer and Kanokporn Noy Rithidech

Int. J. Mol. Sci. 2025, 26(6), 2548; https://doi.org/10.3390/ijms26062548 - 12 Mar 2025

Cited by 3 | Viewed by 3668

Abstract

We used molecular docking to determine the binding energy and interactions of apigenin and 16 related flavonoids, with 24 distinct proteins having diverse biological functions. We aimed to identify potential inhibitors of these proteins and understand the structural configurations of flavonoids impacting their binding energy. Our results demonstrate that apigenin exhibits high binding energies (a surrogate for binding affinity or inhibitory potential) to all tested proteins. The strongest binding energy was −8.21 kcal/mol for p38 mitogen-activated protein kinases, while the weakest was −5.34 kcal/mol for cyclin-dependent kinase 4. Apigenin and many other flavonoids showed high binding energies on xanthine oxidase (1.1–1.5 fold of febuxostat) and DNA methyltransferases (1.1–1.2 fold of azacytidine). We uncovered high binding energies of apigenin and certain flavonoids with mutated Kirsten rat sarcoma viral oncogene homolog at G12D (KRAS G12D), G12V, and G12C. Consequently, apigenin and certain flavonoids have the potential to effectively inhibit pan-KRAS oncogenic activity, not just on specific KRAS mutations. Apigenin and certain flavonoids also have high binding energies with aromatase (involved in estrogen production) and bacterial infections, i.e., DNA gyrase B and 3R-hydroxy acyl-ACP dehydratase (FABZ). Our findings are pivotal in identifying specific flavonoids that can effectively inhibit targeted proteins, paving the way for the development of innovative flavonoid-based drugs. Full article

(This article belongs to the Special Issue Drug Discovery Based on Natural Products)

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16 pages, 4979 KB

Open AccessArticle

Tetrahydrocurcumin Outperforms Curcumin in Preventing Oxidative Stress-Induced Dysfunction in Tert-Butyl Hydroperoxide-Stimulated Cardiac Fibroblasts

by Patrícia dos Santos Azeredo, Charity Fix, Laena Pernomian, Camilla F. Wenceslau, Gerardo G. Piroli, Cristina Pontes Vicente and Wayne E. Carver

Int. J. Mol. Sci. 2025, 26(13), 5964; https://doi.org/10.3390/ijms26135964 - 21 Jun 2025

Viewed by 1441

Abstract

Oxidative stress is a common feature of various pathological conditions, including tissue remodeling and dysfunction. Cardiac fibroblasts, which play a key role in maintaining extracellular matrix homeostasis, are sensitive to oxidative injury. Curcumin and tetrahydrocurcumin are plant-derived polyphenols with antioxidant properties, yet their relative efficacy in preventing oxidative stress–induced dysfunction in cardiac fibroblasts remains unclear. In this study, cardiac fibroblasts were treated with curcumin or tetrahydrocurcumin prior to exposure to tert-butyl hydroperoxide (t-BHP), a widely used inducer of oxidative stress. Cell viability, apoptosis, reactive oxygen species (ROS) production, and Tgfb1 expression were assessed. Both curcuminoids significantly attenuated oxidative stress–induced cell death, decreased cell viability, and reduced Tgfb1 expression. Notably, tetrahydrocurcumin demonstrated superior protective effects across most parameters. These findings suggest that both compounds help mitigate oxidative-stress–induced cellular dysfunction in cardiac fibroblasts and highlight tetrahydrocurcumin as a potentially more effective antioxidant. Further studies are needed to explore their role in the context of tissue remodeling and fibrotic progression. Full article

(This article belongs to the Special Issue Drug Discovery Based on Natural Products)

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24 pages, 1946 KB

Open AccessArticle

Integrated Molecular and Functional Analysis of Hop Ethanolic Extract in Caco-2 Cells: Insights into Inflammation, Barrier Function, and Transport

by Ruben Emmanuel Verhelst and Aleksandra Kruk

Int. J. Mol. Sci. 2025, 26(21), 10608; https://doi.org/10.3390/ijms262110608 - 31 Oct 2025

Cited by 1 | Viewed by 584

Abstract

Hop (Humulus lupulus L.) is a well-known medicinal and brewing plant, yet studies on the biological activity of its complete extracts remain limited. A comprehensive characterization of a full hop ethanolic extract (HLE) was conducted, integrating untargeted HPLC–MS profiling, anti-inflammatory evaluation in an inflammation-induced Caco-2 model, and transport assessment across intestinal epithelial monolayers. After ultrafiltration to remove pyrogenic components, HLE reduced IL-6 secretion in a concentration-dependent manner and decreased IL-8 levels, while mitigating IL-1β–induced barrier disruption as reflected by TEER recovery. HPLC–MS analysis of the basolateral compartment revealed selective permeability of medium-sized bitter-acid derivatives and the presence of three features not detected in the original extract, suggesting metabolic transformation during epithelial passage. Overall, the complete extract exhibited moderate but biologically relevant anti-inflammatory and barrier-protective effects in intestinal epithelial cells. The use of the whole extract, without isolating individual fractions, represents a practical and physiologically meaningful approach that may facilitate its application in the formulation of functional foods or dietary supplements. Full article

(This article belongs to the Special Issue Drug Discovery Based on Natural Products)

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40 pages, 6116 KB

Open AccessReview

The Role of Natural Chalcones and Their Derivatives in Targeting Prostate Cancer: Recent Updates

by Ola J. Hussein, Dana Elkhalifa, Arij Fouzat Hassan, Feras Alali, Ala-Eddin Al Moustafa and Ashraf Khalil

Int. J. Mol. Sci. 2025, 26(24), 12082; https://doi.org/10.3390/ijms262412082 - 16 Dec 2025

Viewed by 231

Abstract

Prostate cancer (PCa) is the second most prevalent cancer among men and a major cause of cancer-related mortality worldwide. Despite an initial favorable response to hormone-based therapies, many patients ultimately develop an advanced and lethal form of the disease, referred to as castration-resistant PCa (CRPC). CRPC is associated with poor prognosis and a lack of effective curative treatments. As a result, new alternatives or improved therapeutic strategies to combat this life-threatening condition are urgently needed. Chalcones, also referred to as 1,3-diphenyl-2-propen-1-ones, have attracted significant attention because of their potent antitumor properties. Owing to their distinctive chemical structure and diverse biological activities, these compounds are promising candidates for treating various cancers, including PCa. Both naturally occurring and synthetically derived chalcones have demonstrated anticancer potential by modulating key cellular processes, including apoptosis, cell cycle regulation, cell migration, invasion, metastasis and angiogenesis, as well as major signaling pathways, such as PI3K/Akt/mTOR, androgen signaling, and NF-κB. This review aims to outline the recent advances in the therapeutic potential of chalcone derivatives in prostate cancer, with a focus on their molecular targets, mechanisms of action, and translational relevance. Full article

(This article belongs to the Special Issue Drug Discovery Based on Natural Products)

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