High-throughput docking for the identification of new influenza A virus polymerase inhibitors targeting the PA–PB1 protein–protein interaction
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Acknowledgments
We gratefully acknowledge financial support provided by FP7 FLUCURE (Ref. 259972) project.
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Integrating molecular modelling methods to advance influenza A virus drug discovery
2021, Drug Discovery TodayStructure-based virtual screening of influenza virus RNA polymerase inhibitors from natural compounds: Molecular dynamics simulation and MM-GBSA calculation
2020, Computational Biology and ChemistryPotent and broad-spectrum cycloheptathiophene-3-carboxamide compounds that target the PA-PB1 interaction of influenza virus RNA polymerase and possess a high barrier to drug resistance
2019, Antiviral ResearchCitation Excerpt :Since these interactions are essential for viral replication and their binding interfaces are highly conserved among IAV and IBV strains (Pérez and Donis, 1995; Ghanem et al., 2007; Stevaert and Naesens, 2016), the disruption of such interactions represents an attractive strategy for the development of anti-influenza drugs with broad activity (Loregian et al., 2002, 2014; Loregian and Palù, 2005; Palù and Loregian, 2013; Stevaert and Naesens, 2016; Massari et al., 2016). The feasibility and the effectiveness of such an approach have been demonstrated by the increasing number of PA-PB1 dissociative inhibitors developed in the last decade (Wunderlich et al., 2009; Wunderlich et al., 2011; Muratore et al., 2012a; Muratore et al., 2012b; Fukuoka et al., 2012; Massari et al., 2013; Kessler et al., 2013; Lepri et al., 2014; Pagano et al., 2014; Tintori et al., 2014; Massari et al., 2015; Trist et al., 2016; Yuan et al., 2016; Desantis et al., 2017; Watanabe et al., 2017; Massari et al., 2017; Zhang et al., 2018; D'Agostino et al., 2018). Among these, we recently reported the discovery of compounds with a cycloheptathiophene-3-carboxamide (cHTC) scaffold as PA-PB1 inhibitors (Desantis et al., 2017).
Synthesis and biological evaluation of a library of hybrid derivatives as inhibitors of influenza virus PA-PB1 interaction
2018, European Journal of Medicinal ChemistryCitation Excerpt :Cluster analysis performed on the whole MD production trajectories coupled with visual inspection clearly indicated that 7g is stable in the PB1 binding site, with a conformation that is highly consistent to that identified by molecular docking (Fig. 5A). The nitrile group of 7g establishes a H-bond interaction with the side chain of Lys643 (to allow comparison with results described in previous works [63,71] residue numbering follows the sequence of A/Wilson-Smith/1933H1N1 strain). The two phenyl rings of the 3-cyano-4,6-diphenylpyridine scaffold are included in a hydrophobic cleft bounded by Pro625, Phe658, Leu666, Trp706, Phe707, and Phe710.
Influenza A virus polymerase: an attractive target for next-generation anti-influenza therapeutics
2018, Drug Discovery TodayCitation Excerpt :Since the detailed structural imformation of the PA–PB1 interaction was determined, in silico screening of PA–PB1 PPI inhibitors has been used widely. Tintori and co-workers first reported a SBVS study aiming to discover novel chemical molecules disturbing PA–PB1 heterodimerization [137]. In particular, the molecular dynamic simulation on the PA–PB1 complex was employed using a protein assembly built from PDB codes C3M8 and 2ZNL to identify the crucial residues (hotspot residues) involved in PA–PB1 interaction.
Hierarchical virtual screening approaches in small molecule drug discovery
2015, MethodsCitation Excerpt :Subsequent scaffold searches identified a series of compounds able to disrupt frataxin/ubiquitin PPI with μM affinity. A similar hierarchical docking approach has been also used to identify inhibitors of PA–PB1 [181], p53–MDM2 [126], Cdc42–intersectin [182] and TWEAK–Fn14 [183] PPI. Using SB-HLVS, Khanna et al. [147] reported the discovery of SMPPIIs inhibiting the uPAR–uPA PPI.