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Advances and Opportunities of Natural Products in Drug Discovery

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: 31 December 2026 | Viewed by 9993

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Prof. Dr. Daniel Pereira Bezerra

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Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, BA, Brazil
Interests: natural products; experimental oncology; biotechnology; natural products biotechnology
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Special Issue Information

Dear Colleagues,

Natural products have long been an important component of drug development, providing structurally diverse and pharmacologically active molecules. Recent improvements in analytical techniques such as high-resolution mass spectrometry, NMR spectroscopy, and genome mining have renewed interest in these substances, enabling the rapid identification and characterization of complex natural molecules. In addition, advances in synthetic biology and metabolic engineering are enabling researchers to maximize the production of natural commodities and derivatives, thereby addressing supply and sustainability concerns.

The incorporation of artificial intelligence and machine learning into natural product research has also provided new opportunities to predict biological activities, discover novel biosynthetic pathways, and accelerate lead optimization. Furthermore, research in underexplored ecosystems such as deep-sea environments, extreme habitats, and microbiomes continues to yield novel bioactive chemicals with potential therapeutic applications.

This Special Issue encourages submissions of original research articles and reviews of natural products in drug discovery. We only accept submissions of chemically well-characterized compounds.

Prof. Dr. Daniel Pereira Bezerra
Guest Editor

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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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

natural products
drug discovery
pharmacological activity
biological activity
new compounds

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Published Papers (9 papers)

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21 pages, 2278 KB

Open AccessArticle

Keap1-Inhibitory Peptides from Ganoderma lucidum Spores: Virtual Enzymolysis, Fragmentomics and Antioxidant Mechanism

by Beibei Chen, Liang He, Qi Huang and Yanbin Wang

Molecules 2026, 31(12), 2157; https://doi.org/10.3390/molecules31122157 - 18 Jun 2026

Viewed by 476

Abstract

Ganoderma lucidum spores protein (GLSP) holds significant potential for providing antioxidant peptides. We employed in silico enzymatic hydrolysis to generate small peptide fragments by specific proteins. Through fast computer screening and molecular docking with Keap1 receptor, we identified two potential antioxidant peptides, KAF (Lys-Ala-Phe) and NDSF (Asn-Asp-Ser-Phe), from 1171 candidates after efficient hydrolysis by pepsin and proteinase K. Molecular docking result showed both of them could bind onto the Leu557, Ala 510 and Val512 of bioactive pockets of Keap1 through hydrogen bonds and NDSF had lower docking energy (−85.6073 kcal/mol). The in vitro antioxidant validation indicated both of them could eliminate DPPH and ABTS radicals dramatically, and NDSF had a stronger scavenging capacity on DPPH (IC₅₀ = 35.1 μg/mL) and ABTS (IC₅₀ = 55.9 μg/mL), respectively. Quantitative chemical analysis further revealed that the key antioxidant active sites of NDSF were located at O18 of Ser amino side chain, and N9 of Lys terminal amino residue for KAF. Furthermore, in the cellular experiments, NDSF and KAF effectively increased the activities of antioxidant enzymes such as SOD, CAT, and GPx, while also reducing the level of MDA. Together, these findings highlight the potential of Ganoderma lucidum spore proteins as a source for the rapid identification of antioxidant peptides. The two selected peptides, therefore, s hold promising prospects for applications in functional foods and health products. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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13 pages, 1870 KB

Open AccessArticle

Glyceryl Trinitrate Enhances Caffeine Cytotoxicity Under Metabolic Stress in Cancer Cells

by Vesna Zeljković, Mirjana Bogavac, Tanja V. Soldatović, Marko Mladenović, Zoran Marković, Elvis Mahmutović and Maja Karaman

Molecules 2026, 31(11), 1946; https://doi.org/10.3390/molecules31111946 - 4 Jun 2026

Viewed by 524

Abstract

Cancer cell metabolism represents a critical therapeutic target, particularly under conditions of metabolic stress induced by glycolysis inhibition. Nitroglycerin (glyceryl trinitrate, GTN), a nitric oxide donor, and 2-deoxy-D-glucose (2-DG), a glycolysis inhibitor, have individually demonstrated anticancer potential through modulation of cellular metabolism and redox balance. In this study, we investigated the cytotoxic and combined effects of GTN and caffeine under 2-DG-induced metabolic stress in human cancer cell lines (HeLa, A549, HT29, and MRC-5). Cell viability was assessed using the sulforhodamine B assay after 24 and 48 h treatments, while drug interactions were evaluated using the Chou–Talalay method and combination index (CI) values. 2-DG alone reduced cell viability in a concentration- and time-dependent manner, with IC₅₀ values ranging from 2.01 to 7.05 mM depending on the cell line and exposure period. The combined treatment further enhanced cytotoxicity, particularly in A549 cells, where viability decreased to approximately 63% after 48 h and the calculated IC₅₀ value for GTN in the presence of caffeine reached 0.143 μM. CI analysis demonstrated synergistic interactions in HeLa and A549 cells (CI < 1), whereas HT29 cells predominantly exhibited antagonistic responses (CI > 1). However, strong synergistic effects were also observed in MRC-5 fibroblasts, indicating limited selectivity toward cancer cells. Molecular docking suggested favorable in silico binding of GTN to aldehyde dehydrogenase 2 (ALDH2) and caffeine to the adenosine A2A receptor. Nevertheless, these findings should be considered exploratory and hypothesis-generating because target expression, enzymatic activity, and pathway activation were not experimentally validated. Overall, the results suggest that GTN enhances caffeine-induced cytotoxicity under metabolically stressed conditions through combined metabolic and redox perturbation, although the magnitude of the response depends on cellular context and warrants further mechanistic investigation. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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17 pages, 2020 KB

Open AccessArticle

Therapeutic Potential of Kinkeliba (Combretum micranthum G. Don) Ethanolic Extract in Chronic DSS-Induced Colitis

by Ibrahima Mamadou Sall, Meriem Aziez, Dragoş Hodor, Alina Diana Haşaş, Mara-Georgiana Haralambie, Semzenisi Ecaterina, Alexia-Teodora Hoța and Alexandru-Flaviu Tăbăran

Molecules 2026, 31(9), 1401; https://doi.org/10.3390/molecules31091401 - 23 Apr 2026

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Abstract

Background: Kinkeliba (Combretum micranthum G. Don), commonly used in West African traditional pharmacopeia for its anti-inflammatory and gastrointestinal properties, remains poorly studied regarding its potential role in the prevention or treatment of ulcerative colitis. Objective: This study evaluated the therapeutic potential of the ethanolic extract of Combretum micranthum (EECM) in a murine model of chronic DSS-induced colitis. Methods: Male C57BL/6 mice were subjected to three cycles of 1.5% DSS administration over nine weeks to induce chronic colitis. EECM was administered orally at 50, 100, or 200 mg/kg during the final week. Disease severity was evaluated using the Disease Activity Index (DAI), colon length, biochemical and hematological markers, along with histopathological and immunohistochemical assessment of colonic tissue. Results: EECM treatment significantly improved clinical parameters and prevented colon shortening in chronic DSS-induced colitis. These improvements were associated with the restoration of serum biochemical and hematological profiles, along with reduced histopathological damage and preservation of colonic tissue architecture. Immunohistochemical analysis further demonstrated decreased CD3-positive T-lymphocyte infiltration in colonic tissue, suggesting modulation of local immune cell responses. Conclusions: These findings highlight the therapeutic potential EECM in ulcerative colitis and support further investigations to elucidate its mechanisms of action and evaluate its efficacy in future translational studies. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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25 pages, 2852 KB

Open AccessArticle

Integrative Evaluation of Kigelia africana Fruit Extract: Broad-Spectrum Anticancer Activity, Synergism with Cisplatin and Mechanistic Insights in Colorectal Carcinoma

by Rositsa Mihaylova, Nikolay Bebrivenski, Dimitrina Zheleva-Dimitrova, Rumyana Simeonova, Nisha Singh, Spiro Konstantinov and Georgi Momekov

Molecules 2026, 31(1), 107; https://doi.org/10.3390/molecules31010107 - 26 Dec 2025

Cited by 1 | Viewed by 1213

Abstract

Kigelia africana (“sausage tree”) is an established medicinal plant in African traditional medicine, now recognized for its diverse bioactive constituents and emerging anticancer potential. This study systematically evaluates Kigelia africana fruit extract (KAE) in an in vitro model of HT-29 colorectal carcinoma cells, focusing on its cytotoxic effects, mechanistic impact on protein expression, and synergy with cisplatin chemotherapy. Across 42 oncology-related proteins, covering cell survival, apoptosis, adhesion, invasion, and signaling, KAE demonstrated extensive but typically moderate modulation, while cisplatin produced more pronounced responses in most markers. Protein changes linked to metastasis, therapy resistance, and survival were broadly suppressed, indicating significant antitumor activity. Notably, co-treatment with KAE and cisplatin in HT-29 cells resulted in marked synergistic cytotoxicity, permitting lower cisplatin doses while maintaining efficacy. LC-HRMS analyses revealed 14 metabolites in the extract, including phenolic acids naphthoquinones and iridoids, which may contribute to these effects. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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17 pages, 5799 KB

Open AccessArticle

Rotation Conformational Effects of Selected Cytotoxic Cardiac Glycosides on Their Interactions with Na⁺/K⁺-ATPase

by Yulin Ren, Peirun Yang, Judith C. Gallucci, Can Wang, Xiaolin Cheng, Sijin Wu and A. Douglas Kinghorn

Molecules 2025, 30(24), 4815; https://doi.org/10.3390/molecules30244815 - 18 Dec 2025

Cited by 1 | Viewed by 925

Abstract

Cardenolides are an important group of steroidal natural products and have been used successfully for the treatment of cardiovascular diseases by targeting Na⁺/K⁺-ATPase (NKA) and found more recently to show potential anticancer activity. Biological investigations indicate that both the C-17 lactone unit and the C-3 saccharide moiety of these compounds play an important role in their interaction with NKA and in manifesting the resultant bioactivities. Interestingly, the crystal structures of several cardenolides show various conformations, due to a rotation of the C-3 saccharide moiety or the C-17 lactone unit. These rotation conformations could affect their binding to NKA and the resultant bioactivities, and thus docking profiles with NKA for several cardenolides, including cryptanoside A, digoxin and its aglycone, digoxigenin, and gitoxin, have been investigated in the present investigation. The results indicate that the binding poses of the rotation conformations of the cardenolides selected are different when they bind to NKA, as indicated by their docking scores calculated. For each compound, the rotation conformations observed could be in a dynamic equilibrium, of which each conformer may interact with NKA differentially, and these rotation conformers could act on NKA cooperatively to lead to a specific bioactivity. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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17 pages, 1713 KB

Open AccessArticle

Bioactive Aromatic Plant Extracts Modulate Metabolism and Inflammation in HeLa Cells

by Sara Silva, Manuela Machado, Manuela Pintado and Eduardo M. Costa

Molecules 2025, 30(22), 4401; https://doi.org/10.3390/molecules30224401 - 14 Nov 2025

Cited by 1 | Viewed by 1193

Abstract

Aromatic plants are rich sources of bioactive compounds with recognized therapeutic potential. This study investigated the phytochemical composition and biological activities of ethanolic extracts from four aromatic species—Thymus vulgaris L. (thyme), Rosmarinus officinalis L. (rosemary), Aloysia citrodora (lemon verbena), and Tanacetum balsamita L. (costmary)—using HeLa human cancer cells as a model. LC–MS analysis identified 28–44 metabolites per species, with phenolic compounds and terpenoids comprising 58–67% of total metabolites. Biological assays demonstrated concentration-dependent inhibition of HeLa cell metabolism down to 150 µg/mL, with rosemary displaying the strongest effects. LDH assays confirmed membrane disruption, most notably for lemon verbena (ca. 80% of release), and cellular proliferation was significantly disrupted by all extracts, most notably for thyme (70% reduction). Under oxidative conditions, costmary, thyme, and lemon verbena reduced intracellular ROS by up to 35% and all extracts suppressed IL-6 secretion, with rosemary showing the strongest anti-inflammatory response, lowering IL-6 levels to near or below the assay’s detection limit. Out of all the extracts, rosemary exhibited the most pronounced effects across cytotoxic, antioxidant, and cytokine assays, suggesting synergistic activity of its phenolic and terpenoid constituents. Multivariate analyses (correlation and PCA) linked specific metabolite classes to bioactivity patterns, providing insight into the mechanistic diversity underlying plant-specific effects. Overall, the results support the potential of these aromatic plants as sources of multifunctional bioactive compounds with anticancer and anti-inflammatory properties. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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18 pages, 8730 KB

Open AccessArticle

Ginsenosides Enhanced Apoptosis of Serum-Free Starved A549 Lung Cancer Cells

by Jiwen Li, Keke Li, Mei Sun, Zhihong Gu, Lei Men, Xiaojie Gong and Zhongyu Li

Molecules 2025, 30(18), 3697; https://doi.org/10.3390/molecules30183697 - 11 Sep 2025

Cited by 1 | Viewed by 2076

Abstract

Lung cancer remains a leading cause of cancer-related mortality worldwide, where conventional chemotherapy is often limited by severe side effects and drug resistance. Ginsenosides, the primary bioactive triterpenoid saponins isolated from the root of Panax ginseng C. A. Mey, have demonstrated potential in combating non-small-cell lung cancer (NSCLC). However, their efficacy under nutrient-deficient conditions remains unclear. This study aimed to investigate the effects of ginsenosides on the growth and death of lung cancer cells under low-nutrient conditions and to explore the underlying mechanisms. A549 cells were divided into two groups: one cultured in 10% serum and another under serum-free conditions, followed by treatment with ginsenosides CK, Rh2(S), and Rg3(S) for 24 h. Cell proliferation and apoptosis were evaluated using a CCK-8 assay, Calcein/PI fluorescence staining, Hoechst 33258 staining, and flow cytometry. Potential targets and signaling pathways of ginsenosides were predicted using network pharmacology and bioinformatics analyses. The mRNA expression of key genes was measured by qRT-PCR, and mitochondrial membrane potential was assessed using JC-1 staining. The results showed that ginsenosides induced dose-dependent apoptosis in serum-starved A549 cells. Bioinformatics analysis suggested the involvement of the PI3K/Akt/FoxO signaling pathway, which was supported by decreased Akt mRNA levels and increased FoxO mRNA expression. Furthermore, mRNA levels of Bim, Caspase-3, Caspase-8, and Caspase-9 were significantly upregulated, accompanied by a loss of mitochondrial membrane potential. These findings indicate that under serum deprivation, ginsenosides enhance apoptosis in A549 cells, likely through the regulation of the PI3K/Akt/FoxO pathway. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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15 pages, 2791 KB

Open AccessArticle

In Vitro and In Vivo Efficacy of the Essential Oil from the Leaves of Annona amazonica R.E. Fries (Annonaceae) Against Liver Cancer

by Maria V. L. de Castro, Milena C. F. de Lima, Gabriela A. da C. Barbosa, Sabrine G. Carvalho, Amanda M. R. M. Coelho, Luciano de S. Santos, Valdenizia R. Silva, Rosane B. Dias, Milena B. P. Soares, Emmanoel V. Costa and Daniel P. Bezerra

Molecules 2025, 30(15), 3248; https://doi.org/10.3390/molecules30153248 - 2 Aug 2025

Viewed by 1453

Abstract

Annona amazonica R.E. Fries (synonyms Annona amazonica var. lancifolia R.E. Fries), popularly known in Brazil as “envireira”, is a tropical tree belonging to the Annonaceae family and is traditionally used as a food source. In this work, the in vitro and in vivo anti-liver cancer effects of essential oil (EO) from A. amazonica leaves were investigated for the first time. The chemical composition of the EO was evaluated via GC–MS and GC–FID. The alamar blue assay was used to evaluate the cytotoxicity of EOs against different cancerous and noncancerous cell lines. Cell cycle analyses, YO-PRO-1/PI staining, and rhodamine 123 staining were performed via flow cytometry in HepG2 cells treated with EO. The in vivo antitumor activity of EO was evaluated in NSG mice that were xenografted with HepG2 cells and treated with EO at a dose of 60 mg/kg. The major constituents (>5%) of the EO were (E)-caryophyllene (32.01%), 1,8-cineole (13.93%), α-copaene (7.77%), α-humulene (7.15%), and α-pinene (5.13%). EO increased apoptosis and proportionally decreased the number of viable HepG2 cells. The induction of DNA fragmentation and cell shrinkage together with a significant reduction in the ΔΨm in EO-treated HepG2 cells confirmed that EO can induce apoptosis. A significant 39.2% inhibition of tumor growth in vivo was detected in EO-treated animals. These data indicate the anti-liver cancer potential of EO from A. amazonica leaves. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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25 pages, 5574 KB

Open AccessReview

Flavonoids from Bee Pollen: Functional Components, Applications, and Limitations

by Ying Zhu, Shuting Pu, Zun Wu, Shaofang Hu, Yan Lin, Peiying Shi, Zhiguo Li, Songkun Su and Xueling Xu

Molecules 2026, 31(13), 2379; https://doi.org/10.3390/molecules31132379 - 6 Jul 2026

Viewed by 378

Abstract

Bee pollen is a mixture of pollen, nectar, and bee saliva. It is rich in bioactive substances, including polysaccharides, flavonoids, carbohydrates, proteins, vitamins, and minerals, conferring high nutritional and pharmacological value. The flavonoids in bee pollen are considered the main components responsible for its active function. Based on a systematic elaboration of the physicochemical properties and classification of bee pollen flavonoids, this review summarizes the preclinical research progress of bee pollen flavonoids in inflammation-related diseases, with a focus on prostatitis, colitis, and neuroinflammation, and analyzes the key bottlenecks limiting their application. It should be noted that the current evidence is primarily derived from pharmacological studies at the cellular and animal levels, and the clinical efficacy in human diseases has not yet been confirmed; their potential effects are mainly established on the basis of biological plausibility and preclinical potential. This review aims to provide a reference for subsequent fundamental research and translational exploration of bee pollen flavonoids and to offer insights for the design of future clinical trials. Full article

(This article belongs to the Special Issue Advances and Opportunities of Natural Products in Drug Discovery)

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