Mining Druggable\nSites in Influenza A Hemagglutinin:\nBinding of the Pinanamine-Based Inhibitor M090

Assessing the binding\nmode of drug-like compounds is key in structure-based\ndrug design. However, this may be challenged by factors such as the\nstructural flexibility of the target protein. In this case, state-of-the-art\ncomputational methods can be valuable to explore the linkages between\nstructural and pharmacological data. Following this strategy, extended\nmolecular dynamics simulations and thermodynamic integration calculations\nare used to examine the binding of the potent antiviral inhibitor\nM090 and related pinanamine-based analogues, covering a 250-fold difference\nin inhibitory potency to the influenza A hemagglutinin, which is essential\nfor virus entry and membrane fusion. This analysis has disclosed the\nhydrophobic shielding effect played by the 3-cyclopropylthiophene\nmoiety in M090. Furthermore, the results support the negative effect\nof the resistance-induced E74<sub>2</sub> → D mutation, which\nshould weaken the binding by increasing the structural flexibility\nof the L2-BS loop. The results pave the way to exploration of the\nantiviral activity of novel compounds.