A Commemorative Special Issue in Honor of Professor Eliezer J. Barreiro: Early Drug Discovery: From Target Identification and Validation to Lead Optimization

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

Deadline for manuscript submissions: 31 January 2027 | Viewed by 9718

Special Issue Editors


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Guest Editor
Laboratory for Analysis and Development of Enzyme Inhibitors, Natural Products Research Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941590, Brazil
Interests: NMR; drug design; FBDD; neglected diseases; natural products
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Guest Editor
Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio®), Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941590, Brazil
Interests: medicinal chemistry; drug metabolism; anti-inflammatory drugs; leishmanicides and anti-tumor drugs; oral hypoglycemic agents

Special Issue Information

Dear Colleagues,

Dedicated to the renowned Professor Eliezer J. Barreiro, this Special Issue honors a visionary and a giant in the field of medicinal chemistry.

Dr. Barreiro, Emeritus Professor of the Federal University of Rio de Janeiro (UFRJ), was the first Brazilian to obtain a PhD in medicinal chemistry, after completing a full PhD at the University of Grenoble under the guidance of Pierre Crabbé em 1978. His leadership and pioneering spirit in medicinal chemistry in Brazil and Latin America are undeniable. He was the Founder of the Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio) at UFRJ and the Founder of the Summer School in Pharmaceutical and medicinal chemistry (EVQFM), which celebrates its 31st uninterrupted edition in 2025. Since the 25th edition, the Summer School has been renamed EVQFM-Professor Eliezer Barreiro. Together with his main scientific disciple, Professor Carlos Alberto Manssour Fraga, he wrote the first book on medicinal chemistry written by Brazilians and published in Portuguese in Brazil.

His scientific contribution can be gauged by carefully reading the over 350 publications in scientific journals authored by Professor Eliezer Barreiro. Throughout his career, he has worked on different projects aimed at the design and synthesis of bioactive compounds for chronic non-communicable diseases, focusing on the identification of hits, lead optimization and the selection of pre-clinical candidates. He has supervised hundreds of Masters and PhD students, many of whom have sparked medicinal chemistry research in Brazil. Professor Barreiro was a full member of the Brazilian Academy of Sciences. His death on April 8, 2024 was felt by the entire Brazilian scientific community, but his story and legacy will continue to inspire new generations of medicinal chemists.

This Special Issue, entitled “A Commemorative Special Issue in Honor of Professor Eliezer J. Barreiro: Early Drug Discovery: From Target Identification and Validation to Lead Optimization”, will be published by the journal Pharmaceuticals.

Drug discovery is a complex, multidisciplinary process that begins with identifying and validating the therapeutic target. At this stage, various strategies based on the structure of the target or ligands can be used to identify compounds. These initial stages are fundamental for establishing solid foundations for developing new drugs, reducing risks and increasing the chances of success in the later clinical phases.

This Special Issue highlights recent advances in medicinal chemistry that are driving the discovery and development of drugs in their initial stages. We invite original and review articles in the following areas:

  • State-of-the-art in different strategies for rational drug design, focusing on the structure of the target protein or ligand, with the addition of contributions and potential on the use of artificial intelligence.
  • Challenges and perspectives for the validation of molecular targets.
  • Phenotype-driven drug discovery.
  • Modern methods of organic synthesis are used to obtain bioactive compounds and drugs.
  • Historical aspects of natural products in drug discovery.
  • Molecular modification strategies applied to analog-based drug discovery.
  • Advances and applications of structural biology and omics in early drug discovery.

Dr. Luzineide Tinoco
Dr. Lídia Lima
Guest Editors

Manuscript Submission Information

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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-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.

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Keywords

  • target validation
  • LBDD
  • FBDD
  • SBDD
  • QSAR
  • artificial intelligence
  • organic synthesis
  • natural product
  • drug discovery
  • medicinal chemistry

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Published Papers (4 papers)

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Research

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21 pages, 3387 KB  
Article
Exploring the Impact of 3-O-Methylquercetin on Wnt/β-Catenin Pathway Activity and Its Potential in Neural Processes
by Kamila Leichtweis, Danilo Predes, Marielly C. Mangelli, Hugo Mauricio, Barbara S. M. de Jesus, Clara F. Charlier, Raquel C. da Silva, Giselle F. Passos, Luiz F. S. Oliveira, Clara O. Nogueira, Samir F. A. Cavalcante, Diego M. Lopes, Rodrigo S. Almeida, Danielle C. Bonfim, Alessandro B. C. Simas, Julia R. Clarke, Pedro S. M. Pinheiro and Jose G. Abreu
Pharmaceuticals 2025, 18(11), 1680; https://doi.org/10.3390/ph18111680 - 6 Nov 2025
Cited by 1 | Viewed by 1494
Abstract
Background: The Wnt/β-catenin signaling pathway plays a pivotal role in embryonic development, maintenance of the central nervous system, and the formation of neuronal circuits. Disruption of this pathway is closely associated with oncogenesis and neurodegenerative diseases, notably Alzheimer’s disease. Flavonoids such as [...] Read more.
Background: The Wnt/β-catenin signaling pathway plays a pivotal role in embryonic development, maintenance of the central nervous system, and the formation of neuronal circuits. Disruption of this pathway is closely associated with oncogenesis and neurodegenerative diseases, notably Alzheimer’s disease. Flavonoids such as quercetin derivatives have emerged as promising neuroprotective agents. This study investigates the impact of 3-O-methylquercetin (3OMQ), a methylated quercetin metabolite, on Wnt/β-catenin signaling and its potential relevance in neurodegenerative disease models. Methods: The ability of 3OMQ to modulate Wnt/β-catenin activity was analyzed using a luciferase-based reporter assay in both neural and non-neural cell lines. Cell viability assays evaluated cytotoxicity at various concentrations. We mapped 3OMQ activity within the pathway using targeted cell signaling experiments. Docking and molecular dynamics simulations suggested glycogen synthase kinase 3β (GSK3β) as a putative target of 3OMQ. Finally, we employed a mouse model of acute amyloid-β oligomer (AβO) toxicity to assess the in vivo effects of 3OMQ on spatial memory and Wnt-related gene expression. Results: We compared the flavonoids quercitrin, quercetin, and 3-O-methylquercitrin (3OMQ) with pharmacologically active compounds in a gene reporter assay (TOPFLASH) using Wnt-sensitive RKO cells treated with Wnt3a-conditioned medium. XAV-939 and PNU-74654 showed inhibitory activity, while BIO, CHIR99021, quercitrin, and 3OMQ enhanced the Wnt/β-catenin pathway. Notably, 3OMQ potentiated this pathway at concentrations 5–10 times lower than quercitrin and outperformed 1 μM BIO at 10 μM without cytotoxicity, highlighting its remarkable potency. Mechanistically, 3OMQ acts downstream of initial membrane activation and upstream of the β-catenin destruction complex. Consistently, molecular docking indicates a strong interaction with GSK3, a central regulator of the pathway. In adult mice, 3OMQ administration prevented AβO-induced recognition memory deficits and favored normalization of Wnt-related gene expression. Conclusions: These findings identify 3OMQ as a potent positive modulator of the Wnt/β-catenin pathway, with both in vitro and in vivo neuroprotective effects. Targeting Wnt signaling with compounds such as 3OMQ holds promise for maintaining neuronal health and developing therapeutic strategies for neurodegenerative conditions. Full article
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15 pages, 2552 KB  
Article
Curcumin-like Compound Inhibits Proliferation of Adenocarcinoma Cells by Inducing Cell Cycle Arrest and Senescence
by Rafael Fonseca, Yasmin dos Santos Louzano, Cindy Juliet Cristancho Ortiz, Matheus de Freitas Silva, Maria Luiza Vieira Felix, Guilherme Álvaro Ferreira-Silva, Ester Siqueira Caixeta, Bruno Zavan, Claudio Viegas, Jr. and Marisa Ionta
Pharmaceuticals 2025, 18(6), 914; https://doi.org/10.3390/ph18060914 - 18 Jun 2025
Cited by 3 | Viewed by 2534
Abstract
Background: Lung cancer is the leading cause of cancer-related death in the male sex worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent type, accounting for 80–85% of cases, and lung adenocarcinoma is the most common and lethal NSCLC subtype, being responsible [...] Read more.
Background: Lung cancer is the leading cause of cancer-related death in the male sex worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent type, accounting for 80–85% of cases, and lung adenocarcinoma is the most common and lethal NSCLC subtype, being responsible for ca. 50% of deaths. Despite new therapeutic strategies, lung cancer mortality rates remain high, highlighting the need for the development of new drugs. Objectives: We investigated the pharmacological potential of a series of curcumin-like compounds using two lung adenocarcinoma cell lines as models. Methods and Results: Cell viability assay led to the identification of PQM-214 as the hit compound, and other methodologies were employed to investigate the mechanisms underlying its antitumor potential, including cell cycle analysis, mitotic index determination, assessment of clonogenic capacity, senescence-associated β-galactosidase and annexin V assays, quantitative PCR, and Western blot analyses. The mechanism of action of PQM-214 was investigated in A549 cells, revealing that it effectively inhibits cell proliferation by inducing cell cycle arrest, apoptosis, or senescence. Cell cycle key regulators were significantly modulated by PQM-214, with cyclin E2, MYC, and FOXM1 being downregulated, while senescence markers such as cyclin D1, CDKN1A (p21), IL-8, TIMP1, and TIMP2 were upregulated. Moreover, Western blot results revealed upregulation of cyclin D1 and p21 in PQM-214-treated samples, with a downregulation of cyclin B. Conclusions: PQM-214 seems to act on different molecular targets in lung adenocarcinoma cells, inhibiting cell proliferation and inducing apoptosis. Further studies will be conducted to explore whether PQM-214 can also act as a senolytic agent, which would reinforce its anticancer potential. Full article
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Review

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20 pages, 5022 KB  
Review
Phosphatidylinositol-3-Kinase (PI3K) and Histone Deacetylase (HDAC) Multitarget Inhibitors: An Update on Clinical and Preclinical Candidates
by Alef D. S. Lima and Lídia M. Lima
Pharmaceuticals 2026, 19(1), 130; https://doi.org/10.3390/ph19010130 - 12 Jan 2026
Viewed by 864
Abstract
Phosphatidylinositol-3-kinases (PI3Ks) constitute an important validated therapeutic class involved in crucial cellular processes, and their dysregulation is associated with cancer initiation and progression. Nonetheless, intrinsic and acquired resistance mechanisms associated with PI3K pathway modulation have underscored the need for alternative therapeutic strategies. In [...] Read more.
Phosphatidylinositol-3-kinases (PI3Ks) constitute an important validated therapeutic class involved in crucial cellular processes, and their dysregulation is associated with cancer initiation and progression. Nonetheless, intrinsic and acquired resistance mechanisms associated with PI3K pathway modulation have underscored the need for alternative therapeutic strategies. In this context, recent studies have shown that simultaneous inhibition of PI3K and histone deacetylases (HDAC) promotes synergistic antitumor effects in different cancer cell lines. HDACs are validated epigenetic targets that are extensively explored in clinical practice and have a pharmacophore with versatility for structural modifications, which facilitates the design of multitarget inhibitors. This review examines the rational design and synthetic evolution of dual PI3K/HDAC inhibitors, an area catalyzed by the development of fimepinostat, the first clinically evaluated agent exhibiting potent and balanced inhibition of both targets. We provide a critical overview of PI3K/HDAC multitarget inhibitors reported in recent years that have progressed to preclinical or clinical investigation, discussing the structural frameworks employed, medicinal chemistry strategies adopted, and structure–activity relationships established. Particular attention is given to advantageous molecular features as well as challenges related to toxicity, pharmacokinetic behavior, and pharmacodynamic modulation. From this comprehensive analysis, we outline key considerations and emerging design principles that may inform the next generation of PI3K/HDAC multitarget drug candidates. Insights derived from the diversity of chemical scaffolds, activity profiles, and selectivity patterns described herein may support the development of innovative therapeutic agents capable of overcoming current limitations in anticancer treatment. Full article
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21 pages, 4294 KB  
Review
Medicinal Chemistry Strategies in Targeting TGF-βR1 Kinase Domain: Unveiling Insights into Inhibitor Structure–Activity Relationship (SAR)
by Nusaiba A. Babiker, Soam Nadeem, Hasan Abu Kariem, Afra Abdul Hameed, Ahmed T. Negmeldin and Eman M. El-labbad
Pharmaceuticals 2025, 18(5), 716; https://doi.org/10.3390/ph18050716 - 13 May 2025
Cited by 3 | Viewed by 4084
Abstract
The transforming growth factor-β (TGF-β) signaling pathway is involved in various cellular functions, including immunological response, extracellular matrix formation, differentiation, growth and development, and cell cycle regulation. The TGF β receptor type 1 (TGF-βR1) has emerged as a key component of this pathway, [...] Read more.
The transforming growth factor-β (TGF-β) signaling pathway is involved in various cellular functions, including immunological response, extracellular matrix formation, differentiation, growth and development, and cell cycle regulation. The TGF β receptor type 1 (TGF-βR1) has emerged as a key component of this pathway, exhibiting significant overexpression in diverse malignancies, including hepatocellular carcinoma, gastric cancer, breast cancer, and colon cancer. Multiple therapeutic targets have been identified for the TGF-β signaling pathway, encompassing antibodies, ligand traps, vaccines, antisense oligonucleotides, and small-molecule TGF-βR1 kinase inhibitors. This review delineates the structural and functional characteristics of the small-molecule TGF-βR1 kinase inhibitors. The inhibitors discussed herein are categorized based on shared pharmacophoric features, notably a five-membered heterocyclic ring linked to three distinct features (R1, R2, and R3). These features interact with amino acids within the selectivity pocket, hinge region, or solvent-exposed area, respectively. These insights contribute to a clearer understanding of the structural requirements for selective TGF-βR1 inhibition. The presented findings in this review article offer a valuable foundation for future drug discovery efforts targeting the TGF-β signaling pathway. Full article
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