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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: closed (31 December 2025) | Viewed by 22355

Special Issue Editors

Dr. Giulia Culletta

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Guest Editor
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90123 Palermo, Italy
Interests: medicinal chemistry; drug design; computational chemistry; drug repurposing; green chemistry
Special Issues, Collections and Topics in MDPI journals
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 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. 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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Related Special Issue

Published Papers (10 papers)

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Research

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15 pages, 4527 KB  
Article
Molecular Docking and MD Modeling Techniques for the Development of Novel ROS1 Kinase Inhibitors
by Mohammad Jahoor Alam, Arshad Jamal, Shaik Daria Hussain, Shahzaib Ahamad, Dinesh Gupta and Ashanul Haque
Pharmaceuticals 2026, 19(2), 229; https://doi.org/10.3390/ph19020229 - 28 Jan 2026
Viewed by 1055
Abstract
Background: Chemotherapy is a cornerstone of cancer treatment; however, resistance to first-line chemotherapeutic agents remains a major challenge. ROS1, one of fifty-eight receptor tyrosine kinases, has been implicated in various cancer subtypes, including glioblastoma, non-small-cell lung cancer, and cholangiocarcinoma. Notably, the Gly2032Arg mutation [...] Read more.
Background: Chemotherapy is a cornerstone of cancer treatment; however, resistance to first-line chemotherapeutic agents remains a major challenge. ROS1, one of fifty-eight receptor tyrosine kinases, has been implicated in various cancer subtypes, including glioblastoma, non-small-cell lung cancer, and cholangiocarcinoma. Notably, the Gly2032Arg mutation in the ROS1 protein has been linked to resistance against the kinase inhibitor crizotinib. Objectives: Given the challenge, we conducted a comprehensive in silico study to identify new drug candidates. Methods: The study starts with modeling the Gly2032Arg-mutated ROS1 protein, followed by structure-based screening of the PubChem database. Results: Out of 1760 molecules screened, we selected the top 4 molecules (PubChem CID: 67463531, 72544946, 139431449, and 139431487) with structural features similar to crizotinib, a high docking score, and drug likeness. To further validate the effectiveness of the identified compounds, we assessed their binding affinity using the Molecular Mechanics with Generalized Born Surface Area (MM-GBSA) scoring method. To underpin the behavior and stability of protein–ligand complexes, 500 ns molecular dynamics (MD) simulations were conducted, and parameters including RMSD, RMSF, and H-bond dynamics were studied and compared. Density functional theory (DFT) at the B3LYP/6-31G* level was performed to elucidate molecular features of the identified compounds. Conclusions: Overall, this study sheds light on a new series of compounds effective against mutated targets, thereby offering a new horizon in this area. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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27 pages, 4953 KB  
Article
Integrative miRNA–mRNA Network and Molecular Dynamics-Based Identification of Therapeutic Candidates for Paroxysmal Nocturnal Hemoglobinuria
by Peng Zhao, Yujie Tang, Xin Sun, Yibo Xi, Haojun Zhang, Jia Xue, Wenqian Zhou, Hongyi Li and Xuechun Lu
Pharmaceuticals 2026, 19(1), 143; https://doi.org/10.3390/ph19010143 - 14 Jan 2026
Viewed by 618
Abstract
Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease characterized primarily by intravascular hemolysis, thrombosis, and bone marrow failure. Complement inhibitors are commonly used in clinical treatment and show limited efficacy, highlighting the urgent need to identify new therapeutic targets [...] Read more.
Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease characterized primarily by intravascular hemolysis, thrombosis, and bone marrow failure. Complement inhibitors are commonly used in clinical treatment and show limited efficacy, highlighting the urgent need to identify new therapeutic targets and explore alternative treatment strategies to provide theoretical guidance for clinical practice. Methods: We established a PNH cell model and constructed an miRNA–mRNA regulatory network to identify key miRNAs and core target genes. Single-cell sequencing data were analyzed to further clarify the critical genes. Finally, integrated drug database analysis identified potential therapeutic agents for PNH, which were validated by molecular docking and molecular dynamics simulations. Results: Using CRISPR/RNP technology, we successfully constructed a PIGA-knockout (PIGA-KO) THP-1 cell model. Differential expression analysis identified 1979 differentially expressed mRNAs (DEmRNAs) and 97 differentially expressed miRNAs (DEmiRNAs). The multiMiR package in R was used to predict the target genes of DEmiRNAs, from which those experimentally validated through dual-luciferase reporter assays were selected. After integration with the DEmRNAs, an miRNA–mRNA regulatory network was constructed, comprising 26 miRNAs and 38 mRNAs. Subsequent miRNA pathway enrichment analysis identified hsa-miR-23a-3p as a key miRNA, with CXCL12, CXCL8, HES1, and TRAF5 serving as core target genes. The integration of single-cell sequencing datasets (PRJNA1061334 and GSE157344) was performed, followed by cell communication and enrichment analysis. This approach, combined with clinical relevance, identified the neutrophil cluster as the key cluster. Intersection analysis of neutrophil cluster differential analysis results with key modules from hdWGCNA further clarified the critical genes. Drug prediction using EpiMed, CMap, and DGIdb identified Leflunomide, Dipyridamole, and Pentoxifylline as potential therapeutic agents. Molecular docking and molecular dynamics simulations showed stable binding of these potential drugs to the critical molecules, indicating a viable molecular interaction foundation. Conclusions: Leflunomide, Dipyridamole, and Pentoxifylline may serve as promising therapeutic agents for PNH, and the hsa-miR-23a-3p/CXCL8 regulatory axis could play a pivotal role in the pathogenesis and progression of PNH. 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, 4992 KB  
Article
Identification of Potential Pteridin Reductase-1 Inhibitors for the Treatment of Leishmaniasis: A Bioinformatics Approach
by Paulo R. da S. R. Júnior, Lúcio R. de Lima, Luciane B. Silva, Ryan S. Ramos, Vitor H. da S. Sanches, Njogu M. Kimani, Gustavo H. G. Trossini, Joaquín M. Campos, Cleison C. Lobato and Cleydson B. R. Santos
Pharmaceuticals 2025, 18(8), 1237; https://doi.org/10.3390/ph18081237 - 21 Aug 2025
Cited by 1 | Viewed by 1391
Abstract
Background/Objectives: Leishmaniasis is an infectious disease caused by digenetic protozoa of the genus Leishmania, transmitted by infected female sandflies of the Phlebotominae subfamily. Current treatments are limited, relying on drugs that were not specifically developed for this disease and are often associated [...] Read more.
Background/Objectives: Leishmaniasis is an infectious disease caused by digenetic protozoa of the genus Leishmania, transmitted by infected female sandflies of the Phlebotominae subfamily. Current treatments are limited, relying on drugs that were not specifically developed for this disease and are often associated with high toxicity and elevated costs. Among alternative therapeutic strategies, antifolate compounds have been investigated due to their ability to inhibit dihydrofolate reductase (DHFR), an enzyme essential for folate metabolism in the parasite. However, the parasite circumvents DHFR inhibition through the activity of pteridine reductase-1 (PTR-1), which maintains folate reduction and ensures parasite survival. In this context, this study aimed to identify potential PTR-1 inhibitors in Leishmania major through in silico approaches. Methods: The methodology included virtual screening of molecular databases, Tanimoto similarity analysis, pharmacokinetic and toxicological predictions, and biological activity evaluation in silico. The most promising compounds were further analyzed via molecular docking. Results: The virtual screening resulted in 474 molecules, of which 4 structures (M601, M692, M700, and M703) showed high potential as PTR-1 inhibitors in Leishmania major throughout all stages of the methodology employed, especially in the results of molecular docking where they exhibited strong binding affinities and significant interactions with key residues of the target enzymes. Conclusions: This work provides a solid foundation for advancing these molecules into experimental validation, contributing to the development of safer and more effective therapeutic alternatives for the treatment of leishmaniasis. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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22 pages, 3211 KB  
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
Cited by 2 | Viewed by 1472
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 KB  
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
Cited by 1 | Viewed by 1725
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 KB  
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
Cited by 1 | Viewed by 1956
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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30 pages, 1549 KB  
Review
Pharmaceutical Strategies for West Nile Virus in Europe, an Underrecognized Cause of Severe Disease and Mortality in Older Adults: From Supportive Care to Antiviral Development
by Luca Soraci, Leonardo Biscetti, Andrea Corsonello, Edlin Villalta Savedra, Guido Gembillo, Filippo Luciani, Alessia Beccacece, Maria Princiotto, Emanuele Nicastri, Laura Ponzetta, Alessandra D’Abramo, Gioberto Filice, Martina Napoli and Maria Elsa Gambuzza
Pharmaceuticals 2026, 19(2), 302; https://doi.org/10.3390/ph19020302 - 11 Feb 2026
Viewed by 1058
Abstract
West Nile Virus (WNV) is becoming a significant and enduring public health menace in Europe, propelled by climate changes and accelerated population aging. Most infections are asymptomatic but older adults are more prone to develop neuroinvasive disease, which is characterized by high morbidity [...] Read more.
West Nile Virus (WNV) is becoming a significant and enduring public health menace in Europe, propelled by climate changes and accelerated population aging. Most infections are asymptomatic but older adults are more prone to develop neuroinvasive disease, which is characterized by high morbidity and mortality, as well as long-term neurological disturbances and disability. To date, there is still no licensed human vaccine or specific antiviral treatment, and management is mostly supportive. This review brings together the most recent information about WNV epidemiology, pathogenesis, and clinical manifestations, with a special focus on older people in Europe. We critically analyze current and novel pharmaceutical strategies, encompassing drug repurposing, nucleoside analogues, interferon-based therapies, peptides, monoclonal antibodies, and host-directed agents, emphasizing their therapeutic potential alongside the challenges presented by age-related pharmacokinetic and immunological alterations. We also discuss some important gaps in the current evidence base, such as the frequent exclusion of older adults from clinical studies and the lack of a coordinated clinical trial infrastructure that can be quickly activated during seasonal outbreaks. Lastly, we suggest a framework that combines systematic antiviral screening with the creation of a Europe-wide network of clinical trial readiness that is built into current One Health surveillance systems. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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18 pages, 1818 KB  
Review
Docking in the Dark: Insights into Protein–Protein and Protein–Ligand Blind Docking
by Muhammad Sohaib Roomi, Giulia Culletta, Lisa Longo, Walter Filgueira de Azevedo, Jr., Ugo Perricone and Marco Tutone
Pharmaceuticals 2025, 18(12), 1777; https://doi.org/10.3390/ph18121777 - 22 Nov 2025
Cited by 6 | Viewed by 2088
Abstract
Blind docking predicts binding interactions between two molecular entities without prior knowledge of the binding site. This approach is essential because it explores the entire surface of the receptor to identify potential interaction sites. Blind docking widely works for both protein–protein and ligand–protein [...] Read more.
Blind docking predicts binding interactions between two molecular entities without prior knowledge of the binding site. This approach is essential because it explores the entire surface of the receptor to identify potential interaction sites. Blind docking widely works for both protein–protein and ligand–protein interaction studies. In protein–protein blind docking, the method aims to predict the correct orientation and interface of two proteins forming a complex. Protein blind docking is particularly valuable in studying transient interactions, protein–protein recognition, signaling pathways, tentative and significant biomolecular assemblies where structural data is limited. Ligand–protein blind docking discovers potential binding pockets across the entire protein surface. It is frequently applied in early-stage drug discovery, especially for novel or poorly characterized targets. The method helps identify allosteric sites or novel binding regions that are not evident from known structures. Overall, blind docking provides a versatile and powerful tool for studying molecular interactions, enabling discovery even in the absence of detailed structural information. In this scenario, we reported a timeline of attempts to improve this kind of computational approach with ML and hybrid approaches to obtain more reliable predictions. We dedicate two main sections to protein–protein and protein-ligand blind docking, presenting the reliability and caveats for each approach and outlining potential future directions. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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15 pages, 1506 KB  
Review
Computational Chemistry Advances in the Development of PARP1 Inhibitors for Breast Cancer Therapy
by Charmy Twala, Penny Govender and Krishna Govender
Pharmaceuticals 2025, 18(11), 1679; https://doi.org/10.3390/ph18111679 - 6 Nov 2025
Cited by 1 | Viewed by 1795
Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) is an important enzyme that plays a central role in the DNA damage response, facilitating repair of single-stranded DNA breaks via the base excision repair (BER) pathway and thus genomic integrity. Its therapeutic relevance is compounded in breast [...] Read more.
Poly (ADP-ribose) polymerase 1 (PARP1) is an important enzyme that plays a central role in the DNA damage response, facilitating repair of single-stranded DNA breaks via the base excision repair (BER) pathway and thus genomic integrity. Its therapeutic relevance is compounded in breast cancer, particularly in BRCA1 or BRCA2 mutant cancers, where compromised homologous recombination repair (HRR) leaves a synthetic lethal dependency on PARP1-mediated repair. This review comprehensively discusses the recent advances in computational chemistry for the discovery of PARP1 inhibitors, focusing on their application in breast cancer therapy. Techniques such as molecular docking, molecular dynamics (MD) simulations, quantitative structure–activity relationship (QSAR) modeling, density functional theory (DFT), time-dependent DFT (TD-DFT), and machine learning (ML)-aided virtual screening have revolutionized the discovery of inhibitors. Some of the most prominent examples are Olaparib (IC50 = 5 nM), Rucaparib (IC50 = 7 nM), and Talazoparib (IC50 = 1 nM), which were optimized with docking scores between −9.0 to −9.3 kcal/mol and validated by in vitro and in vivo assays, achieving 60–80% inhibition of tumor growth in BRCA-mutated models and achieving up to 21-month improvement in progression-free survival in clinical trials of BRCA-mutated breast and ovarian cancer patients. These strategies enable site-specific hopping into the PARP1 nicotinamide-binding pocket to enhance inhibitor affinity and specificity and reduce off-target activity. Employing computation and experimental verification in a hybrid strategy have brought next-generation inhibitors to the clinic with accelerated development, higher efficacy, and personalized treatment for breast cancer patients. Future approaches, including AI-aided generative models and multi-omics integration, have the promise to further refine inhibitor design, paving the way for precision oncology. Full article
(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)
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25 pages, 7873 KB  
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 20 | Viewed by 8214
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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