Work

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

Year: 2024

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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 E74 2 → 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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.4c00502

Authors: Aitor Valdivia, Maria Rocha, F. Javier Luque

Institutions: Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, University of Coimbra

Language: English

Topic: Influenza Virus Research Studies

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500