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Volume 30
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Discovery of Influenza Neuraminidase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation of Novel Chemotypes

by
Rosaria Gitto
1,*,
Lisa Lombardo
1,
Angela Ravenda
1,
Francesco Broccolo
2,
Antonio Mastino
3,
Laura De Luca
1 and
Francesca Marino-Merlo
1
1
CHIBIOFARAM Department, University of Messina, Viale F. d’Alcontres 31, I-98166 Messina, Italy
2
DiMeS Department of Experimental Medicine, University of Salento, Ecotekne Center, S.P6 Monteroni, I-73047 Lecce, Italy
3
The Institute of Translational Pharmacology, CNR, Via Fosso del Cavaliere 100, I-00133 Roma, Italy
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(23), 4636; https://doi.org/10.3390/molecules30234636 (registering DOI)
Submission received: 31 October 2025 / Revised: 24 November 2025 / Accepted: 29 November 2025 / Published: 2 December 2025
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation—3rd Edition)
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Abstract

Neuraminidase (NA) decorates the surface of the influenza virus, exerting a sialidase activity that enables the viral particle to be released in the host cell. Numerous sialic-based antiviral agents competitively bind to the NA cavity and are marketed worldwide for the treatment of Influenza A infection. We designed and validated a structure-based pharmacophore model for influenza neuraminidase (NA), which guided a virtual screening campaign against an in-house library of compounds already available for testing. This fast and cost-effective in silico strategy resulted in the identification of seven candidates possessing indole or isoquinoline chemical core. In vitro assays confirmed their favorable cytotoxicity profiles and identified only one, the 1-(1H-indol-3-ylcarbonyl)-3-piperidinecarboxylic acid (1), with reproducible inhibitory activity toward NA at non-cytotoxic concentrations. This work suggested a validated workflow for the discovery of novel NA inhibitors and highlighted an indole-based hit compound as a starting point for further optimization.
Keywords: neuraminidase; anti-flu agents; NAIs; MD simulation; pharmacophore modeling; flexible docking; virtual screening neuraminidase; anti-flu agents; NAIs; MD simulation; pharmacophore modeling; flexible docking; virtual screening
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MDPI and ACS Style

Gitto, R.; Lombardo, L.; Ravenda, A.; Broccolo, F.; Mastino, A.; De Luca, L.; Marino-Merlo, F. Discovery of Influenza Neuraminidase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation of Novel Chemotypes. Molecules 2025, 30, 4636. https://doi.org/10.3390/molecules30234636

AMA Style

Gitto R, Lombardo L, Ravenda A, Broccolo F, Mastino A, De Luca L, Marino-Merlo F. Discovery of Influenza Neuraminidase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation of Novel Chemotypes. Molecules. 2025; 30(23):4636. https://doi.org/10.3390/molecules30234636

Chicago/Turabian Style

Gitto, Rosaria, Lisa Lombardo, Angela Ravenda, Francesco Broccolo, Antonio Mastino, Laura De Luca, and Francesca Marino-Merlo. 2025. "Discovery of Influenza Neuraminidase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation of Novel Chemotypes" Molecules 30, no. 23: 4636. https://doi.org/10.3390/molecules30234636

APA Style

Gitto, R., Lombardo, L., Ravenda, A., Broccolo, F., Mastino, A., De Luca, L., & Marino-Merlo, F. (2025). Discovery of Influenza Neuraminidase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation of Novel Chemotypes. Molecules, 30(23), 4636. https://doi.org/10.3390/molecules30234636

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