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Viruses
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Advances in Small-Molecule Viral Inhibitors
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Advances in Small-Molecule Viral Inhibitors

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 15 July 2025 | Viewed by 440

Special Issue Editor

Dr. Chiara Bertagnin

E-Mail Website
Guest Editor
Department of Molecular Medicine, University of Padua, Via A. Gabelli 63, 35121 Padua, Italy
Interests: small-molecule inhibitors; protein–protein interaction inhibitors; antiviral discovery; emerging viruses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viral diseases still represent a terrible threat to public health due to the continuous emergence and re-emergence of different viruses that might cause epidemics or pandemics, as we recently experienced with SARS-COV-2. Despite many research efforts, many viral diseases still suffer from a lack of therapeutic measures.

Small-molecule inhibitors represent a potent tool in this scenario, as they can be designed to target and inhibit specific viral proteins, receptors, or enzymes involved in infectious processes. Such compounds usually have a molecular weight lower than 1000-1500 Da, allowing them to easily penetrate the cell membrane and thus target also intracellular components. The development of small-molecule antivirals is an important field of research that is continuously growing, thanks to the advances in medicinal chemistry and targeted screening strategies and the increasing availability of compounds’ virtual libraries.

For this Special Issue of Viruses, authors are encouraged to submit their latest findings and results on the characterization of small-molecule antivirals as original research papers. Presented data may include in vitro and in vivo or translational studies. Reviews summarizing the existing body of literature in this field are also welcome.

Dr. Chiara Bertagnin
Guest Editor

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. Viruses 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 2600 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-molecule inhibitors
  • PROTACs
  • antiviral compounds
  • drug discovery
  • protein–protein interaction inhibitors
  • enzymatic inhibitors

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Published Papers (2 papers)

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Research

25 pages, 2250 KiB  
Article
Antagonistic Trends Between Binding Affinity and Drug-Likeness in SARS-CoV-2 Mpro Inhibitors Revealed by Machine Learning
by Anacleto Silva de Souza, Vitor Martins de Freitas Amorim, Eduardo Pereira Soares, Robson Francisco de Souza and Cristiane Rodrigues Guzzo
Viruses 2025, 17(7), 935; https://doi.org/10.3390/v17070935 - 30 Jun 2025
Abstract
The SARS-CoV-2 main protease (Mpro) is a validated therapeutic target for inhibiting viral replication. Few compounds have advanced clinically, underscoring the difficulty in optimizing both target affinity and drug-like properties. To address this challenge, we integrated machine learning (ML), molecular docking, and molecular [...] Read more.
The SARS-CoV-2 main protease (Mpro) is a validated therapeutic target for inhibiting viral replication. Few compounds have advanced clinically, underscoring the difficulty in optimizing both target affinity and drug-like properties. To address this challenge, we integrated machine learning (ML), molecular docking, and molecular dynamics (MD) simulations to investigate the balance between pharmacodynamic (PD) and pharmacokinetic (PK) properties in Mpro inhibitor design. We developed ML models to classify Mpro inhibitors based on experimental IC50 data, combining molecular descriptors with structural insights from MD simulations. Our Support Vector Machine (SVM) model achieved strong performance (training accuracy = 0.84, ROC AUC = 0.91; test accuracy = 0.79, ROC AUC = 0.86), while our Logistic Regression model (training accuracy = 0.78, ROC AUC = 0.85; test accuracy = 0.76, ROC AUC = 0.83). Notably, PK descriptors often exhibited opposing trends to binding affinity: hydrophilic features enhanced binding affinity but compromised PK properties, whereas hydrogen bonding, hydrophobic, and π–π interactions in Mpro subsites S2 and S3/S4 are fundamental for binding affinity. Our findings highlight the need for a balanced approach in Mpro inhibitor design, strategically targeting these subsites may balance PD and PK properties. For the first time, we demonstrate antagonistic trends between pharmacokinetic (PK) and pharmacodynamic (PD) features through the integrated application of ML/MD. This study provides a computational framework for rational Mpro inhibitors, combining ML and MD to investigate the complex interplay between enzyme inhibition and drug likeness. These insights may guide the hit-to-lead optimization of the novel next-generation Mpro inhibitors of SARS-CoV-2 with preclinical and clinical potential. Full article
(This article belongs to the Special Issue Advances in Small-Molecule Viral Inhibitors)
16 pages, 4997 KiB  
Communication
Broad-Spectrum Antiviral Activity of Pyridobenzothiazolone Analogues Against Respiratory Viruses
by Elisa Feyles, Tommaso Felicetti, Irene Arduino, Massimo Rittà, Andrea Civra, Luisa Muratori, Stefania Raimondo, David Lembo, Giuseppe Manfroni and Manuela Donalisio
Viruses 2025, 17(7), 890; https://doi.org/10.3390/v17070890 - 24 Jun 2025
Viewed by 195
Abstract
Cell-based phenotypic screening of a privileged in-house library composed of pyridobenzothiazolone (PBTZ) analogues was conducted against representative viruses responsible for common respiratory tract infections in humans, i.e., respiratory syncytial virus (RSV), human coronavirus type OC43 (HCoV-OC43), and influenza virus type A (IFV-A). We [...] Read more.
Cell-based phenotypic screening of a privileged in-house library composed of pyridobenzothiazolone (PBTZ) analogues was conducted against representative viruses responsible for common respiratory tract infections in humans, i.e., respiratory syncytial virus (RSV), human coronavirus type OC43 (HCoV-OC43), and influenza virus type A (IFV-A). We identified a compound with broad-spectrum inhibitory activity against multiple strains of RSV, HCoV, and IFV, with EC50 values in the low micromolar range and cell-independent activity. Its antiviral activity and cytocompatibility were confirmed in a fully differentiated 3D model of the bronchial epithelium mimicking the in vivo setting. The hit compound enters cells and localizes homogeneously in the cytosol, inhibiting replicative phases in a virus-specific manner. Overall, the selected PBTZ represents a good starting point for further preclinical development as a broad-spectrum antiviral agent that could address the continuous threat of new emerging pathogens and the rising issue of antiviral resistance. Full article
(This article belongs to the Special Issue Advances in Small-Molecule Viral Inhibitors)
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