Novel inhibitors of influenza sialidases related to GG167 structure-activity, crystallographic and Molecular dynamics studies with 4H-pyran-2-carboxylic acid 6-carboxamides

• Published in: Bioorganic & medicinal chemistry letters 1996-12, Vol.6 (24), p.2931-2936
• Main Authors: Smith, Paul W., Sollis, Steven L., Howes, Peter D., Cherry, Peter C., Cobley, Kevin N., Taylor, Helen, Whittington, Andrew R., Scicinski, Jan, Bethell, Richard C., Taylor, Neil, Skarzynski, Tadeusz, Cleasby, Anne, Singh, Oncar, Wonacott, Alan, Varghese, Jose, Colman, Peter
• Format: Article
• Language: English
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(96)00542-2

The structure-activity relationships of a series of 4-amino and guanidino-4H-pyran-2-carboxylic acid 6-carboxamides are described. These compounds represent a new class of inhibitor of influenza sialidases and are particularly active against influenza A sialidase. The binding of the N-phenethyl-N-propylamide 41 to influenza A and B sialidases has been investigated using X-ray crystallography and molecular dynamics simulations. Our results suggest that formation of a hitherto unobserved intramolecular salt bridge within the enzymes may account for the observed activity and selectivity of the series. SAR and the binding mode of a novel series of carboxamide influenza sialidase inhibitors related to GG167 have been investigated. A hitherto unobserved intramolecular salt bridge within the influenza sialidases accounts for the observed activity and selectivity.