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Pharmaceuticals
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Secondary Metabolites as Drug Leads: Bridging Experimental Discovery and Computational...
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Secondary Metabolites as Drug Leads: Bridging Experimental Discovery and Computational Innovation

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

Deadline for manuscript submissions: 25 June 2026 | Viewed by 2370

Special Issue Editors

Dr. Alberto Jorge Oliveira Lopes

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Guest Editor
Graduate Program in Chemistry, Federal Institute of Education, Science, and Technology of Maranhão, São Luis 65030-005, MA, Brazil
Interests: medicinal chemistry; natural products; bioinformatics; biological activity
Special Issues, Collections and Topics in MDPI journals
Dr. Francisco das Chagas Alves Lima

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Departamento de Química, Universidade Estadual do Piauí, Rua João Cabral 2231, Pirajá, Teresina 64002-150, PI, Brazil
Interests: molecular docking; molecular dynamics; calculations of bioinorganic; metal complexes; rational drug design
Dr. Antônio José Cantanhede Filho

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Guest Editor
Laboratório de Extração e Cromatografia, Instituto Federal de Educação, Ciência e Tecnologia do Maranhão, Campus Monte Castelo, São Luís 65030-005, MA, Brazil
Interests: metabolic routes; endophytic fungi; Isolation; identification; secondary metabolites; plants and microorganisms
Special Issues, Collections and Topics in MDPI journals
Dr. Luisa Di Paola

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Guest Editor
Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, Università Campus Bio-Medico of Rome, 00128 Rome, Italy
Interests: medicinal chemistry; natural products; drug discovery and design; computational biology; allosteric drugs
Dr. Robert Vianello

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Guest Editor
Laboratory for the Computational Design and Synthesis of Functional Materials, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
Interests: computational chemistry; protein-ligand interactions; reaction mechanisms; structure-based drug design; electronic structure calculations; molecular dynamics simulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Secondary metabolites, derived from plants, microorganisms, and marine organisms, have long been a cornerstone in efforts toward the discovery of novel therapeutic agents, owing to their structural diversity and wide spectrum of biological activities. Recent advances in computational chemistry and bioinformatics, synergistically combined with experimental methodologies, have significantly enhanced the identification, characterisation, and optimisation of these bioactive compounds.

This Special Issue will provide an interdisciplinary platform for research in this area, emphasising the critical importance of integrating computational strategies with experimental validation to elucidate mechanisms of action, predict pharmacokinetic profiles, and optimise therapeutic efficacy. This approach aligns directly with the scope of Pharmaceuticals, promoting a multidisciplinary perspective that bridges medicinal chemistry, pharmacology, biotechnology, and computational sciences. By showcasing integrative studies, this Special Issue will stimulate significant scientific contributions and foster innovation in secondary metabolite research, ultimately advancing the development of safer and more effective therapeutic agents.

Dr. Alberto Jorge Oliveira Lopes
Dr. Francisco das Chagas Alves Lima
Dr. Antônio José Cantanhede Filho
Dr. Luisa Di Paola
Dr. Robert Vianello
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

  • medicinal chemistry
  • computer aided-drug design
  • new drugs agents
  • natural products

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Published Papers (2 papers)

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Research

21 pages, 9972 KB  
Article
Silibinin Potentiates Antimicrobial Action and Reduces Staphyloxanthin in Staphylococcus aureus
by José Lima Pereira-Filho, Amanda Graziela Gonçalves Mendes, Carmem Duarte Lima Campos, Viviane da Silva Sousa Almeida, Aleania Polassa Almeida Pereira, Israel Viegas Moreira, Cinara Regina Aragão Vieira Monteiro, Louriane Nunes Gomes, Cristianne Roberta Rhoden, Antonio José Cantanhede-Filho, Lucilene Amorim Silva, Alberto Jorge Oliveira Lopes, Rafael Cardoso Carvalho and Valério Monteiro-Neto
Pharmaceuticals 2026, 19(4), 643; https://doi.org/10.3390/ph19040643 - 18 Apr 2026
Viewed by 445
Abstract
Background/Objectives: The emergence of methicillin-resistant Staphylococcus aureus (MRSA) necessitates innovative strategies to overcome conventional resistance mechanisms. This study investigated the potential of the natural flavonolignan silibinin (SIL) as an antivirulence agent against S. aureus, with a particular emphasis on its putative multi-target [...] Read more.
Background/Objectives: The emergence of methicillin-resistant Staphylococcus aureus (MRSA) necessitates innovative strategies to overcome conventional resistance mechanisms. This study investigated the potential of the natural flavonolignan silibinin (SIL) as an antivirulence agent against S. aureus, with a particular emphasis on its putative multi-target antibacterial activity and its capacity to potentiate the effects of ciprofloxacin (CIP). Methods: The antibacterial and antivirulence properties of SIL were assessed using both in vitro and in silico approaches. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined, and its synergistic interaction with CIP was evaluated using checkerboard assays. Inhibition of biofilm formation, as well as disruption of established biofilms, was assessed using an MTT-based viability assay. Staphyloxanthin (STX) inhibition was examined through pigment extraction and spectrophotometric quantification of pathway intermediates. Molecular docking studies were conducted to predict the binding affinities of the compounds to key bacterial targets, while safety was evaluated through haemolytic and cytotoxicity assays. Results: SIL exhibited weak to moderate direct antibacterial activity (MICs of 256–512 µg/mL), which is characteristic of many natural product scaffolds. Notably, SIL potentiated the activity of CIP, reducing its MIC by up to fourfold against selected resistant strains of S. aureus. SIL significantly inhibited biofilm formation and disrupted established mature biofilms in a strain-dependent manner. In vitro metabolic profiling and in silico analyses provided mechanistic insights into the effects of SIL on STX biosynthesis. Precursor accumulation data suggest inhibition at the diapophytoene desaturase (CrtN) catalytic step, representing a potential mechanism not previously reported for flavonolignans. Molecular docking studies further predicted favourable binding affinities for CrtM and other key targets. Importantly, SIL exhibited no haemolytic activity and low cytotoxicity in macrophages at synergistic concentrations. Conclusions: This study provides evidence that SIL functions as a dual-action agent, potentiating ciprofloxacin efficacy while reducing STX production and inhibiting biofilm formation, thereby impairing key virulence mechanisms of S. aureus. These findings, together with its favourable safety profile, provide a strong rationale for the development of silibinin-based topical adjuvants to combat drug-resistant Staphylococcus infections in humans. Full article
(This article belongs to the Special Issue Secondary Metabolites as Drug Leads: Bridging Experimental Discovery and Computational Innovation)
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15 pages, 1379 KB  
Article
Molecular Interaction and Biological Activity of Fatty Acids and Sterols: An In Silico and In Vitro Approach Against Haemonchus contortus
by Susan Yaracet Páez-León, Alexandre Cardoso-Taketa, Abraham Madariaga-Mazón, Adriana Morales-Martínez, Juan Felipe de Jesús Torres-Acosta, Gabriela Mancilla-Montelongo, Víctor Manuel Hernández-Velázquez, Gabriel Navarrete-Vázquez, Elba Villegas and Liliana Aguilar-Marcelino
Pharmaceuticals 2026, 19(1), 140; https://doi.org/10.3390/ph19010140 - 14 Jan 2026
Viewed by 1507
Abstract
Background: Haemonchus contortus is a gastrointestinal nematode that affects small ruminants and exhibits widespread resistance to commercial anthelmintics. This has driven interest in natural compounds such as fatty acids and sterols; however, their biological relevance against resistant parasite strains remains insufficiently understood. [...] Read more.
Background: Haemonchus contortus is a gastrointestinal nematode that affects small ruminants and exhibits widespread resistance to commercial anthelmintics. This has driven interest in natural compounds such as fatty acids and sterols; however, their biological relevance against resistant parasite strains remains insufficiently understood. Methods: The nematicidal potential of four fatty acids (palmitic, linoleic, pentadecanoic, and stearic acids) and two sterols (β-sitosterol and ergosterol), all of them commercially available in Mexico, was evaluated against infective L3 larvae of a benzimidazole-resistant H. contortus strain. In vitro larval mortality and migration inhibition assays were performed, and molecular docking analyses were conducted to explore interactions with the glutamate-gated chloride channel (GluCl) using AutoDock4. Statistical analyses were performed using ANOVA followed by Tukey’s post hoc test (p < 0.05). Results: Molecular docking indicated strong binding affinities of ergosterol and β-sitosterol to GluCl, comparable to that of ivermectin. In vitro assays showed that fatty acids, particularly linoleic acid, produced more pronounced effects on larval motility, suggesting predominantly nematostatic activity. No clear dose–response relationship was observed in migration assays, and in vitro mortality remained limited across treatments. Conclusions: The results highlight a disconnect between in silico binding affinity and in vitro biological activity, particularly in a drug-resistant H. contortus strain. Integrating in vitro bioassays with computational approaches provides valuable mechanistic insight but also underscores the limitations of affinity-based predictions for assessing anthelmintic efficacy. Full article
(This article belongs to the Special Issue Secondary Metabolites as Drug Leads: Bridging Experimental Discovery and Computational Innovation)
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