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30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry

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

Deadline for manuscript submissions: 31 December 2026 | Viewed by 11142

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Prof. Dr. Raffaele Saladino

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Guest Editor

Department of Ecological and Biological Sciences, Tuscia University, 01100 Viterbo, Italy
Interests: organic chemistry; bioorganic chemistry; chemistry of natural substances and catalysis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Harri Lönnberg

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Guest Editor

Department of Chemistry, University of Turku, 20014 Turku, Finland
Interests: kinetic studies on chemical models of ribonucleases and ribozymes; synthesis and application of oligonucleotide conjugates; pro-drug strategies for phosphoester drugs; novel approaches for medium-scale synthesis of oligonucleotides
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The year 2026 will mark the 30th anniversary of Molecules, and to celebrate this important milestone, we are pleased to announce the Special Issue entitled “30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry”, dedicated to highlighting cutting-edge research in the field of bioorganic chemistry.

Bioorganic chemistry lies at the interface of organic chemistry and the life sciences, focusing on the chemical principles underlying biological processes and the design, synthesis, and functional study of biologically relevant molecules. This interdisciplinary field encompasses the development of chemical tools to probe biological systems, the synthesis of complex biomolecules and biomimetic structures, and the exploration of molecular interactions that govern biological function and regulation.

The aim of this Special Issue is to showcase recent high-quality advances and emerging trends in bioorganic chemistry contributed by researchers from diverse scientific backgrounds. Particular emphasis is placed on molecular-level studies that deepen our understanding of enzyme function, catalysis, molecular recognition, biomolecular interactions, and the chemical basis of biological signaling and regulation.

Contributions to this Special Issue may include—but are not limited to—research on chemoenzymatic and biomimetic synthesis, biocatalysis and biosynthetic pathways, enzyme inhibitors and immobilization strategies, functional proteins and peptides, non-natural amino acids, glycobiology, bioactive lipids, nucleic acid recognition, neurotoxins and receptor interactions, immunochemical techniques, supramolecular and membrane chemistry, as well as advanced analytical and mass spectrometry-based studies of biomolecules. Both fundamental studies and applied research with clear biological or biomedical relevance are welcome.

We warmly invite researchers working across the broad and dynamic field of bioorganic chemistry to contribute their latest findings to this celebratory Special Issue, thereby helping to commemorate the 30-year legacy of Molecules and to shape its future scientific impact.

Prof. Dr. Raffaele Saladino
Prof. Dr. Harri Lönnberg
Guest Editors

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-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.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

bioorganic chemistry
chemoenzymatic synthesis
biocatalysis
biomimetic synthesis
biomolecular interactions
functional biomolecules
molecular recognition

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Published Papers (9 papers)

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Research

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26 pages, 7138 KB

Open AccessArticle

CO₂-Extract-Based Phytopreparation from Arctium tomentosum Mill. Root Exhibits No Acute and Subacute Toxicity and Suppresses Xylene-Induced Ear Edema and LPS-Induced Acute Inflammation in Mice

by Arailym Aitynova, Moldyr Dyusebaeva, Diana Issayeva, Gulzat Berganayeva, Nailya Ibragimova, Alya Berganayeva, Tamara Shalakhmetova and Bogdan Sevastre

Molecules 2026, 31(11), 1900; https://doi.org/10.3390/molecules31111900 - 1 Jun 2026

Cited by 1 | Viewed by 396

Abstract

A phytopreparation based on the CO₂ extract of Arctium tomentosum Mill. root (AT) was evaluated for its safety and anti-inflammatory potential in Swiss albino mice. Acute and 28-day subacute oral toxicity studies demonstrated that AT, at doses up to 5000 mg/kg (acute) and 400 mg/kg (subacute), did not induce mortality, clinical signs of toxicity, or adverse effects on body weight, relative organ weights, or hematological and biochemical parameters. Histopathological analyses confirmed preserved tissue architecture in major organs, indicating the absence of structural toxicity. Anti-inflammatory activity was assessed using xylene-induced ear edema and LPS-induced systemic inflammation models. AT significantly reduced ear edema and suppressed the production of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in a dose-dependent manner. Additionally, AT exhibited potent hepatoprotective and nephroprotective effects, as reflected by the stabilization of ALT, AST, SCr, and BUN levels. Histological examination of inflamed tissues corroborated these findings. Overall, AT is well tolerated and demonstrates potent systemic anti-inflammatory and multi-organ protective properties, supporting its potential as a promising therapeutic candidate for inflammatory and oxidative stress-related conditions. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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36 pages, 1933 KB

Open AccessArticle

Populus nigra Bud Extract as a Standardized Alternative to Propolis: Evidence of Compositional Similarity—Functional Properties of an Oral Spray Containing Populus nigra Bud Extract

by Luisa Mattoli, Andrea Lugli, Michela Burico, Giada Fodaroni, Denise Decarli, Mattia Gianni, Anna Maidecchi, Giulia Antonini, Silvia Tondi, Anna Gaetano, Valentina Fiordelli, Rita Pagiotti, Jacopo Lucci, Claudio Buttarini, Stefano Garetto, Raffaele Saladino, Donatella Pietrella, Valentina Mercati and Emiliano Giovagnoni

Molecules 2026, 31(11), 1836; https://doi.org/10.3390/molecules31111836 - 26 May 2026

Viewed by 748

Abstract

Populus nigra buds contain resinous exudates rich in flavonoids, phenolic acids, terpenoids and other bioactive constituents. These exudates are the main botanical source of European Poplar-type propolis. Since hive-collected propolis shows strong botanical, geographical and hive contaminant variability, P. nigra bud resin exudate represents an attractive, standardizable and reproducible alternative for obtaining natural-complex ingredients. This study investigates the compositional relationship between Propolgemma^® standardized P. nigra buds (PBHE) and European propolis (PHE) hydroalcoholic extracts through integrated analytical approaches and evaluates the functional bioactivity of PBHE and a related oral spray formulation (Propolgemma^® spray forte, PBHE-SF). Untargeted metabolomic fingerprinting revealed clear clustering of P. nigra bud exudate with European propolis, demonstrating high compositional similarity. Targeted analyses confirmed that PBHE belongs to the poplar-type propolis family, while retaining additional bud-derived constituents such as salicylates, lignins and tannins, typical of bud tissue and largely absent from hive-collected propolis. Functionally, PBHE showed concentration-dependent antioxidant activity and significant inhibition of Streptococcus pyogenes biofilm at sub-MIC levels. PBHE, incorporated into a patented oral spray formulation (PBHE-SF), demonstrated strong mucoadhesion, high resistance to salivary wash-off, retention of antioxidant flavonoids on epithelial substrates and a mechanical barrier effect, reducing LPS-induced IL-6 release by 39%. It also showed dispersion of pre-formed S. pyogenes biofilms. PBHE emerges as a reproducible, plant-derived, bee-independent alternative to European propolis. Its chemical consistency, functional reliability, independence from bee foraging and from hive-derived contaminants improve the therapeutic potential on mucosal protection in medical device formulations and the suitability for scalable, controlled and industrially sustainable production. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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22 pages, 4318 KB

Open AccessArticle

Rapid Discovery of CD38 Inhibitor via DNA-Encoded Natural Product Library Screening

by Xinyu Shi, Ze Liang, Wentao Meng, Guang Yang and Lei Yan

Molecules 2026, 31(5), 864; https://doi.org/10.3390/molecules31050864 - 5 Mar 2026

Cited by 2 | Viewed by 1501

Abstract

CD38 is a multifunctional enzyme that plays a pivotal role in NAD⁺ metabolism and calcium signaling, and its abnormal activity is closely associated with multiple myeloma, age-related metabolic decline, neurodegenerative diseases, and other disorders. Although monoclonal antibodies such as daratumumab have been approved for clinical application, their inherent limitations necessitate the development of novel small-molecule CD38 inhibitors. In this study, we employed DNA-encoded library (DEL) technology for the high-throughput screening of CD38 inhibitors, using a DEL library containing more than 100,000 unique compounds to screen against recombinant human CD38. A total of 1043 enriched compounds were initially identified, and after rigorous validation and screening to exclude non-specific binding and previously reported active compounds, eight hit compounds with diverse chemical scaffolds were obtained, among which Fenbendazole—a clinically approved antiparasitic drug—was included. Surface plasmon resonance (SPR) assays confirmed the direct binding of these hit compounds to CD38, with dissociation constants (KD) ranging from 7.74 × 10⁻⁵ M to 2.15 × 10⁻⁴ M. Fluorescence-based enzymatic activity assays demonstrated that these compounds exert dose-dependent inhibitory effects on both the hydrolase (with ε-NAD as substrate) and cyclase (with NGD as substrate) activities of CD38. Further structure–activity relationship (SAR) analysis of Fenbendazole analogues revealed the critical structural features that regulate CD38 inhibitory potency, and Flubendazole was found to exhibit excellent inhibitory activity, with an IC₅₀ of 14.78 ± 4.21 μM against CD38 hydrolase and 26.31 ± 3.40 μM against cyclase. Molecular docking and 100 ns molecular dynamics (MD) simulations further elucidated the molecular mechanism of CD38 inhibition by lead compounds, confirming that van der Waals interactions are the main driving force for the binding of small-molecule ligands to CD38, with conserved aromatic residues in the active site mediating ligand recognition. This study validates DEL technology as an efficient and reliable platform for the discovery of CD38 inhibitors, and the identified lead compounds—especially Fenbendazole and its analog Flubendazole—provide valuable molecular scaffolds for the further structural optimization of CD38 inhibitors. These findings lay a solid foundation for the development of novel therapeutic agents for the treatment of CD38-associated diseases. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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19 pages, 4940 KB

Open AccessArticle

Impact of C-Terminal Amide N-Derivatization on the Conformational Dynamics and Antimitotic Activity of Cemadotin Analogues

by Dayana Alonso, Daniel Platero-Rochart, Pauline Stark, Leonardo G. Ceballos, Robert Rennert, Daniel G. Rivera, Julieta Coro-Bermello and Ludger A. Wessjohann

Molecules 2026, 31(5), 825; https://doi.org/10.3390/molecules31050825 - 28 Feb 2026

Viewed by 831

Abstract

Tubulin is a heterodimeric protein composed of α- and β-subunits, which polymerize to form the cell’s microtubules. The latter are key components in mitotic spindle formation and essential targets in anticancer therapy. Compounds such as paclitaxel, tubulysins, dolastatins and synthetic analogues of these latter compounds, including cemadotin, exert their cytotoxic effects by disrupting microtubule dynamics. Previously, we reported the production and anticancer activity of a library of cemadotin analogues featuring a C-terminal tertiary amide functionalized with a variety of N-substituents, thus resulting in compounds occurring as a mixture of amide rotamers. Here we describe a comprehensive NMR and conformational study that provides new insights into the effect of the conformational equilibrium on the binding mode of the novel cemadotin analogues to the tubulin target. The conformational behavior of the isomer equilibrium of cemadotin’s terminal amide bond was investigated by TOCSY and ROESY NMR experiments, which allowed the identification and quantification of individual rotamer populations. A slow interconversion between the s-cis and s-trans amide rotamers was observed under standard NMR conditions (25 °C), indicating a significant energy barrier and conformational rigidity. Molecular docking and saturation transfer difference (STD) NMR experiments were performed with a representative analogue and tubulin to assess the binding mode. The results revealed that the s-trans rotamer is the predominant conformer in solution and exhibits a more favorable interaction with tubulin compared to the s-cis isomer, thus helping to understand the conformational requirements for an improved tubulin binding and the inhibition of the polymerization process. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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17 pages, 2499 KB

Open AccessArticle

Inhibition of Histone Lysine Acetyltransferases by Coenzyme A Analogs

by Faidra Voukia, Nurgül Bilgin, Steffen Bundgaard Andersen and Jasmin Mecinović

Molecules 2026, 31(3), 477; https://doi.org/10.3390/molecules31030477 - 29 Jan 2026

Viewed by 996

Abstract

Histone lysine acetylation is a widespread posttranslational modification, essential for vital functions in eukaryotic organisms. Histone lysine acetyltransferases (KATs) employ acetyl-coenzyme A as a universal acetyl donor for acetylation of lysine residues in histone and non-histone proteins. Despite the biomedicinal importance of modulation of the KAT activity, application of the acetyl-coenzyme A cosubstrate structure for the design of potent and selective inhibitors has been underexplored. Here, we developed functionalized coenzyme A analogs as inhibitors against human histone lysine acetyltransferases GCN5, KAT8, and HAT1. In contrast to the unmodified coenzyme A, which was found to be a poor inhibitor of GCN5 and KAT8 (IC₅₀ > 150 μM), we showed that a ketone-substituted coenzyme A was the most potent inhibitor of GCN5 and KAT8 (IC₅₀ = 10.9 μΜ and 13.6 μΜ, respectively). Coenzyme A and an acetamide-substituted coenzyme A efficiently inhibited HAT1 (IC₅₀ = 7.3 μΜ and IC₅₀ = 3.9 μΜ, respectively). Our work demonstrates that human KATs can be efficiently and selectively inhibited by S-functionalized coenzyme A, the results exhibiting significant potential towards development of highly active chemical probes for biomedically important KATs. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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17 pages, 2175 KB

Open AccessArticle

Efficient Degradation of Monoacylglycerols by an Engineered Aspergillus oryzae Lipase: Synergistic Effects of sfGFP Fusion and Rational Design

by Yuqing Wang, Fang Liu, Yuxi Tian, Jiazhen Sun, Dawei Liu, Fei Li, Yaping Wang and Ben Rao

Molecules 2026, 31(3), 398; https://doi.org/10.3390/molecules31030398 - 23 Jan 2026

Viewed by 775

Abstract

Monoacylglycerols (MAGs) are significant intermediate byproducts in the hydrolysis of oils and fats. The accumulation of MAGs not only reduces the quality and purity of the final products in biodiesel production and edible oil refining but also poses challenges for downstream separation processes. Therefore, the development of efficient biocatalysts for the specific MAG conversion is of great industrial importance. The lipase from Aspergillus oryzae (AOL) has shown potential for lipid modification; however, the wild-type enzyme (WT) suffers from poor solubility, tendency to aggregate, and low specific activity towards MAGs in aqueous systems, which severely restricts its practical application. In this study, a combinatorial protein engineering strategy was employed to overcome these limitations. We integrated fusion protein technology with rational design to enhance both the functional expression and catalytic efficiency of AOL. Firstly, the superfolder green fluorescent protein (sfGFP) was fused to the N-terminus of AOL. The results indicated that the sfGFP fusion tag significantly improved the solubility and stability of the enzyme, preventing the formation of inclusion bodies. The fusion protein sfGFP-AOL exhibited a MAG conversion rate of approximately 65%, confirming the positive impact of the fusion tag on enzyme developability. To further boost catalytic performance, site-directed mutagenesis was performed based on structural analysis. Among the variants, the mutant sfGFP-Y92Q emerged as the most potent candidate. In the MAG conversion, sfGFP-Y92Q achieved a conversion rate of 98%, which was not only significantly higher than that of sfGFP-AOL but also outperformed the widely used commercial immobilized lipase, Novozym 435 (~54%). Structural modeling and docking analysis revealed that the Y92Q mutation optimized the geometry of the active site. The substitution of Tyrosine with Glutamine at position 92 likely enlarged the substrate-binding pocket and altered the local electrostatic environment, thereby relieving steric hindrance and facilitating the access of the bulky MAG substrate to the catalytic center. In conclusion, this work demonstrates that the synergistic application of sfGFP fusion and rational point mutation (Y92Q) can dramatically transform the catalytic properties of AOL. The engineered sfGFP-Y92Q variant serves as a robust and highly efficient biocatalyst for MAG degradation. Its superior performance compared to commercial standards suggests immense potential for cost-effective applications in the bio-manufacturing of high-purity fatty acids and biodiesel, offering a greener alternative to traditional chemical processes. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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Review

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22 pages, 1622 KB

Open AccessReview

Human Neutrophil Elastase and the Protein-Storm Axis: Reversible Synthetic Inhibitors in Inflammatory Disease

by Simona Viglio, Maria Antonietta Grignano, Marilena Gregorini, Teresa Rampino, Giampiero Pietrocola and Paolo Iadarola

Molecules 2026, 31(9), 1441; https://doi.org/10.3390/molecules31091441 - 27 Apr 2026

Cited by 1 | Viewed by 927

Abstract

Human neutrophil elastase (HNE) is a central mediator of neutrophil-driven inflammation. Yet, despite decades of research and drug development, therapies targeting HNE have not consistently translated into clear clinical benefits. We suggest that this translational gap partly arises from how HNE has traditionally been conceptualized, as a single enzyme to inhibit. In biological systems, however, HNE operates within a complex and tightly regulated network of proteases and inflammatory mediators. This network is spatially compartmentalized and strongly influenced by local redox conditions, making HNE activity highly context-dependent. From a systems perspective, HNE acts as an amplifier of inflammation. Its extracellular activity connects several pathological processes, including activation of innate immunity, extracellular matrix degradation, disruption of epithelial and endothelial barriers, and the transition toward chronic inflammation. In this review, we integrate insights from enzymology, systems biology, and clinical research to reassess the development of HNE inhibitors, ranging from endogenous antiproteases to more recent reversible synthetic compounds. Despite their chemical and pharmacological diversity, many of these strategies have encountered similar limitations. We therefore argue that future therapeutic approaches should move beyond the inhibition of HNE as an isolated target and instead aim to modulate the broader protease network, with particular attention to drug–target kinetics and precise delivery to disease-relevant microenvironments. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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30 pages, 1596 KB

Open AccessReview

β-Glucuronidase at the Microbiota—Host Interface: Dual Regulatory Roles and Precision Modulation by Natural Products

by Jialu Shen, Shuai Xu, Qingyu Zhao, Junmin Zhang and Huiyan Zhang

Molecules 2026, 31(4), 601; https://doi.org/10.3390/molecules31040601 - 9 Feb 2026

Cited by 3 | Viewed by 2293

Abstract

Gut microbial β-glucuronidase (GUS) plays a pivotal role at the microbiota—host interface by hydrolyzing glucuronide conjugates, thereby influencing xenobiotic metabolism, enterohepatic circulation, and systemic homeostasis. Dysregulated GUS activity has been increasingly linked to adverse health outcomes, including drug-induced toxicity, inflammation, and cancer. However, current literature often overlooks the enzyme’s dual role in maintaining physiological balance and promoting disease progression, as well as the multidimensional ways in which natural products interact with GUS. This work reviews recent advances in GUS research, emphasizing its structural diversity, functional complexity, and regulatory impact on host health. It also highlights the potential of natural products as precision modulators of GUS activity, capable of direct enzyme inhibition or indirect modulation through reshaping the gut microbiota. These mechanisms collectively influence drug efficacy, toxicity, and the systemic availability of endogenous metabolites. By integrating structural, pharmacological, and microbiological perspectives, this work provides a theoretical foundation for the development of microbiota-targeted therapies centered on GUS. Such approaches may support the rational design of natural product-derived inhibitors and promote their application in disease models, ultimately advancing personalized therapeutic strategies. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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22 pages, 4000 KB

Open AccessReview

Enhancing Tumor Photodynamic Therapy via Molecular Engineering and Functional Modification of Photosensitizers

by Wei Zheng, Linlin Tao, Xiaofeng Xia, Tianlin Wang and Feiyi Wang

Molecules 2026, 31(3), 560; https://doi.org/10.3390/molecules31030560 - 5 Feb 2026

Cited by 5 | Viewed by 1471

Abstract

Photosensitizers are susceptible to interference from the biological internal environment, which largely restricts the clinical application of photodynamic therapy. For instance, most existing photosensitizers tend to aggregate in the biological environment, resulting in a decrease in reactive oxygen species yield; their therapeutic efficacy is unsatisfactory in hypoxic tumor environments; they are difficult to accumulate effectively in tumor sites and cannot accurately distinguish between tumors and healthy tissues. To address these issues, this review systematically elaborates on a series of optimization strategies, including improving the intersystem crossing efficiency of photosensitizers through molecular engineering, endowing them with aggregation-induced emission properties, developing type I photosensitizers, and functionalizing photosensitizers by modifying biological proteins, targeting groups, or combining with nanoengineering, aiming to enhance the efficiency of photodynamic therapy. By summarizing the latest research breakthroughs, innovative methods, and emerging applications in this field, the review provides practical solutions and broad application prospects for photodynamic therapy, which is expected to promote the clinical translation and application of photosensitizers. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Bioorganic Chemistry)

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