Abstract
The matrix protein 1 (M1) of influenza A virus (IAV) exists as a three-dimensional oligomeric structure in mature virions with high sequence conservation across different IAV subtypes, which makes it a potential broad spectrum antiviral target. We hypothesized that impairing self-association of M1 through a small molecule ‘wedge’, which avidly binds to an M1-M1 interface, would result in a completely new class of anti-influenza agents. To establish this proof-of-principle, we performed virtual screening on a library of >70,000 commercially available small molecules that resulted in several plausible ‘wedges’. Biophysical studies showed that the best molecule bound the M1 protein potently and weakened M1-M1 self-association. Most importantly, the agent reduced the thickness of the M1 layer in mature virions and inhibited in ovo propagation of multiple IAV strains including H1N1, pandemic H1N1, H3N2 and H5N1, which supports the “wedge” hypothesis. These results demonstrate that M1 is a promising druggable target for the discovery of a completely new line of broad spectrum anti-IAV agents.
Highlights
Virtual libraries of ready-to-dock structures representing the LOPAC and Maybridge databases were downloaded from ZINC[50]
Primary amino acid sequences corresponding to the M1 protein and the M2 proton channel were downloaded from the NCBI Influenza Resource Database[46]
Virtual libraries of ready-to-dock structures representing the LOPAC and Maybridge databases were downloaded from ZINC50
Summary
Virtual libraries of ready-to-dock structures representing the LOPAC and Maybridge databases were downloaded from ZINC (http://zinc.docking.org)[50]. Virtual screening was accomplished using GOLD Suite 5.151 and the Goldscore fitness function with default parameters; the top-scoring solution was retained for each ligand. The ligand binding site was defined to encompass a 12 Å radius about the Cα atom of E152, located at the center of the negatively charged surface on the “N” face of the M1 protein. This binding site definition covers major grooves on this side, as well as the hydrophobic pocket on the “H” face. Up to ten docking runs were performed for each ligand, with early termination enabled such that docking terminated when the best three solutions found were all within 1.5 Å RMS
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