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Pharmaceuticals
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Drug Target Exploration and Drug Design & Development Based on...
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Drug Target Exploration and Drug Design & Development Based on Small Molecule

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 31 December 2025 | Viewed by 5368

Special Issue Editors

Dr. Giulia Culletta

E-Mail Website
Guest Editor
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
Interests: synthetic medicinal chemistry; computational medicinal chemistry; anticancer compounds; translational readthrough-inducing drugs (TRIDs); nonsense mutations; natural compounds; drug repurposing
Dr. Marco Tutone

E-Mail Website
Guest Editor
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
Interests: oxidative stress; nutraceuticals; anticancer drugs; medicinal chemistry; drug design and discovery; molecular modeling; QSAR; pharmacophore modeling; molecular dynamics; docking; HTVS; cystic fibrosis translational readthrough inducing drugs (TRIDs)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of novel therapeutics represents a significant area of scientific interest, with small-molecule compounds offering a promising frontier in this field of research. On a global scale, approximately 90% of all drugs sold are small molecules. Of the 293 new chemical entities that the FDA approved in 2017–22, 182 were small-molecule drugs (10.1016/j.med (idd.2020.100075). It is also known that of all the 175 small molecules approved for cancer therapy from 1940 to 2014, 49% (85) were natural products or their derivatives, and these include vinca alkaloids, epipodophyllotoxin derivatives, taxanes, and camptothecin derivatives (https://doi.org/10.1007/s42977-022-00110-x).

The ability of small molecules to modulate the functionality of diverse targets (proteins or nucleic acids) through the process of activation or inhibition provides a potential strategy for the treatment of conditions such as cancer, autoimmune disorders, infectious diseases, and inflammatory diseases (10.3390/ijms21155262).

The recent advancements in medicinal chemistry have facilitated the identification and development of small molecules by using classical and green methods. Moreover, the application of computational approaches such as docking and molecular dynamics has been crucial in the exploration of potential targets, including those that are traditionally considered 'undruggable' or orphans (https://doi.org/10.3390/books978-3-0365-2778-9). This Special Issue aims to provide a comprehensive overview of the latest advances in the research on drug target exploration as well as drug design and development based on small molecules. We welcome submissions from researchers in the field of drug discovery and design, including original research and review articles related to pharmaceutical sciences, pharmacology, chemical biology, and bioinformatics. 

Dr. Giulia Culletta
Dr. Marco Tutone
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 100 words) can be sent to the Editorial Office for announcement on this website.

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • small molecules
  • drug design and development
  • target exploration
  • anticancer drugs
  • anti-inflammatory drugs
  • neuromodulation
  • natural compounds
  • nutraceuticals
  • virtual screenings

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Published Papers (4 papers)

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Research

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22 pages, 3211 KiB  
Article
Synthesis and Cytotoxic Activity of a New Family of α-Hydroxyphosphonates with the Benzothiophene Scaffold
by Mátyás Milen, Tamás Miklós John, Anna Sára Kis, Zsófia Garádi, Zsuzsanna Szalai, Angéla Takács, László Kőhidai, Konstantin Karaghiosoff and György Keglevich
Pharmaceuticals 2025, 18(7), 949; https://doi.org/10.3390/ph18070949 - 24 Jun 2025
Viewed by 468
Abstract
Background: α-Hydroxyphosphonates, one of the most prominent classes of phosphonates, remain of utmost importance because of their potential and real biological activity as pharmaceutical or pesticide agents. The effect is the consequence of their enzyme inhibitory properties. Objectives: It was planned [...] Read more.
Background: α-Hydroxyphosphonates, one of the most prominent classes of phosphonates, remain of utmost importance because of their potential and real biological activity as pharmaceutical or pesticide agents. The effect is the consequence of their enzyme inhibitory properties. Objectives: It was planned to make available new heterocyclic hydroxyphosphonate derivatives with cytotoxic activity. Methods: After optimizing the synthesis, 23 members of a new family, α-hydroxy-α-(benzothiophen-2-yl)-methylphosphonates, were prepared by the Pudovik reaction of benzo[b]thiophene-2-carboxaldehydes and diethyl phosphite. The addition was performed at 26 °C in the presence of triethylamine as the catalyst. One of the products was also characterized by single-crystal X-ray analysis. Results: The cytotoxic effect of the α-hydroxy-α-benzothiophenyl-methylphosphonates was tested on U266 myeloma, A2058 melanoma, HT-29 colon, and EBC-1 lung cancer cell lines. Most of the molecules showed significant activity; the greatest effects were seen after treatment with hydroxyphosphonates with a trifluoromethyl group in the benzene ring. Conclusions: The cytotoxic activity of the newly synthesized α-hydroxyphosphonates is encouraging to find even better derivatives. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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24 pages, 3712 KiB  
Article
Elucidation of Artemisinin as a Potent GSK3β Inhibitor for Neurodegenerative Disorders via Machine Learning-Driven QSAR and Virtual Screening of Natural Compounds
by Hassan H. Alhassan, Malvi Surti, Mohd Adnan and Mitesh Patel
Pharmaceuticals 2025, 18(6), 826; https://doi.org/10.3390/ph18060826 - 31 May 2025
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Abstract
Background/Objectives: Glycogen synthase kinase-3 beta (GSK3β) is a key enzyme involved in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, contributing to tau hyperphosphorylation, amyloid-beta (Aβ) aggregation, and neuronal dysfunction. Methods: This study applied a machine learning-driven virtual screening approach to identify potent [...] Read more.
Background/Objectives: Glycogen synthase kinase-3 beta (GSK3β) is a key enzyme involved in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, contributing to tau hyperphosphorylation, amyloid-beta (Aβ) aggregation, and neuronal dysfunction. Methods: This study applied a machine learning-driven virtual screening approach to identify potent natural inhibitors of GSK3β. A dataset of 3092 natural compounds was analyzed using Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbors (KNN), with feature selection focusing on key molecular descriptors, including lipophilicity (ALogP: −0.5 to 5.0), hydrogen bond acceptors (0–10), and McGowan volume (0.5–2.5). RF outperformed SVM and KNN, achieving the highest test accuracy (83.6%), specificity (87%), and lowest RMSE (0.3214). Results: Virtual screening using AutoDock Vina and molecular dynamics simulations (100 ns, GROMACS 2022) identified artemisinin as the top GSK3β inhibitor, with a binding affinity of −8.6 kcal/mol, interacting with key residues ASP200, CYS199, and LEU188. Dihydroartemisinin exhibited a binding affinity of −8.3 kcal/mol, reinforcing its neuroprotective potential. Pharmacokinetic predictions confirmed favorable drug-likeness (TPSA: 26.3–70.67 Å2) and non-toxicity. Conclusions: While these findings highlight artemisinin-based inhibitors as promising candidates, experimental validation and structural optimization are needed for clinical application. This study demonstrates the effectiveness of machine learning and computational screening in accelerating neurodegenerative drug discovery. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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24 pages, 1755 KiB  
Article
Exploring the Anticancer Properties of 1,2,3-Triazole-Substituted Andrographolide Derivatives
by Joana R. L. Ribeiro, Juliana Calheiros, Rita A. M. Silva, Bruno M. F. Gonçalves, Carlos A. M. Afonso, Lucília Saraiva and Maria-José U. Ferreira
Pharmaceuticals 2025, 18(5), 750; https://doi.org/10.3390/ph18050750 - 19 May 2025
Viewed by 774
Abstract
Background/Objectives: The search for new anticancer agents from natural sources remains a key strategy in drug discovery. This study aimed to synthesize and evaluate novel triazole derivatives of the diterpenic lactone andrographolide for their antiproliferative activity against various cancer cell lines. Methods [...] Read more.
Background/Objectives: The search for new anticancer agents from natural sources remains a key strategy in drug discovery. This study aimed to synthesize and evaluate novel triazole derivatives of the diterpenic lactone andrographolide for their antiproliferative activity against various cancer cell lines. Methods: Twenty-two new triazole derivatives (5–26), of the triacetyl derivative (2) of the diterpenic lactone andrographolide (1), were synthesized via the azide-alkyne “click reaction”. The antiproliferative effects of compounds 1–26 were evaluated using the sulforhodamine B assay against a panel of cancer cell lines and a non-tumorigenic colon cell line. A representative compound, triazole derivative 12, was further evaluated in human pancreatic ductal adenocarcinoma (PANC-1) cells for its effects on the cell cycle, apoptosis, migration, and drug synergy with 5-fluorouracil. Results: Several compounds, specifically, 9, 14, 16, and 17, bearing a phenyl moiety, exhibited improved antiproliferative activity compared to the parental compound 1. Derivative 12, selected for further investigation, induced G2/M cell cycle arrest and apoptosis in a concentration-dependent manner. Additionally, this compound significantly reduced cell migration and demonstrated synergistic effects with 5-fluorouracil in PANC-1 cells. Conclusions: The synthesized andrographolide-based triazole derivatives, particularly compound 12, showed promising antiproliferative activity and mechanisms relevant to cancer therapy. These findings support their potential as lead compounds for further development in anticancer research. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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Review

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25 pages, 7873 KiB  
Review
Recent Developments of 1,3,4-Thiadiazole Compounds as Anticancer Agents
by Serena Indelicato, David Bongiorno, Manuela Mauro and Stella Cascioferro
Pharmaceuticals 2025, 18(4), 580; https://doi.org/10.3390/ph18040580 - 16 Apr 2025
Cited by 1 | Viewed by 3049
Abstract
The World Health Organization has recently underlined the increasing global burden of cancer, with a particularly alarming impact on underserved populations. In recent years, 1,3,4-thiadiazole has emerged as a versatile pharmacophore to obtain bioactive compounds. The pharmacological properties of this ring are primarily [...] Read more.
The World Health Organization has recently underlined the increasing global burden of cancer, with a particularly alarming impact on underserved populations. In recent years, 1,3,4-thiadiazole has emerged as a versatile pharmacophore to obtain bioactive compounds. The pharmacological properties of this ring are primarily attributed to its role as a bioisostere of pyrimidine, the core structure of three nucleic bases. This structural feature endows 1,3,4-thiadiazole derivatives with the ability to interfere with DNA replication processes. Additionally, the mesoionic behavior of this heterocycle gives it important properties, such as the ability to cross biological membranes and interact with target proteins. Noteworthy, in analogy to the other sulfur heterocycles, the presence of C-S σ* orbitals, conferring small regions of low electron density on the sulfur atom, makes interaction with the target easier. This review focuses on the most promising anticancer agents with 1,3,4-thiadiazole structure reported in the past five years, providing information that may be useful to medicinal chemists who intend to develop new anticancer derivatives. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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