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2024-11-28

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cc-by (c) Valdivia, 2024
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/218040

Mining Druggable Sites in Influenza A Hemagglutinin: Binding of the Pinanamine-Based Inhibitor M090

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Recurs relacionat

https://doi.org/10.1021/acsmedchemlett.4c00502

Resum

Assessing the binding mode of drug-like compounds is key in structure-based drug design. However, this may be challenged by factors such as the structural flexibility of the target protein. In this case, state-of-the-art computational methods can be valuable to explore the linkages between structural and pharmacological data. Following this strategy, extended molecular dynamics simulations and thermodynamic integration calculations are used to examine the binding of the potent antiviral inhibitor M090 and related pinanamine-based analogues, covering a 250-fold difference in inhibitory potency to the influenza A hemagglutinin, which is essential for virus entry and membrane fusion. This analysis has disclosed the hydrophobic shielding effect played by the 3-cyclopropylthiophene moiety in M090. Furthermore, the results support the negative effect of the resistance-induced E742 → D mutation, which should weaken the binding by increasing the structural flexibility of the L2-BS loop. The results pave the way to exploration of the antiviral activity of novel compounds. 

Matèries

Influenzavirus, Química farmacèutica

Matèries (anglès)

Influenza viruses, Pharmaceutical chemistry

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Col·leccions

Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)

Citació

VALDIVIA, Aitor, ROCHA, Maria and LUQUE GARRIGA, F. Xavier. Mining Druggable Sites in Influenza A Hemagglutinin: Binding of the Pinanamine-Based Inhibitor M090. ACS Medicinal Chemistry Letters. 2024. Vol. 16, num. 1, pags. 126-135. ISSN 1948-5875. [consulted: 3 of August of 2026]. Available at: https://hdl.handle.net/2445/218040

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