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

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 24, 1996, Pages 2931-2936

  Smith, Paul W ^a   Sollis, Steven L ^a   Howes, Peter D ^a   Cherry, Peter C ^a   Cobley, Kevin N ^a   Taylor, Helen ^a   Whittington, Andrew R ^a   Scicinski, Jan ^a   Bethell, Richard C ^a   Taylor, Neil ^a   Skarzynski, Tadeusz ^a   Cleasby, Anne ^a   Singh, Oncar ^a   Wonacott, Alan ^a   Varghese, Jose ^b   Colman, Peter ^b  

^a GLAXOSMITHKLINE   (United Kingdom)

^b CSIRO   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; SIALIDASE; SIALIDASE INHIBITOR; ZANAMIVIR;

ANTIVIRAL ACTIVITY; ARTICLE; COMPUTER SIMULATION; CONTROLLED STUDY; DRUG SYNTHESIS; ENZYME BINDING; ENZYME INHIBITION; IN VITRO STUDY; INFLUENZA VIRUS A; INFLUENZA VIRUS B; MOLECULAR DYNAMICS; QUANTITATIVE STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

EID: 0030591866     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(96)00542-2     Document Type: Article

References (10)

1. 1. Whittington, A. R.; Bethell, R.C. Exp Opin Ther Patents. 1995, 5, 793.
2. 2. Hayden, F.G; Treanor, J.J; Betts, R.F; Lobo, M.; Esinhart, J.; Hussey, E. J Amer Med Assoc. 1996, 275, 295.
3. 3. Varghese, J.N.; Epa, V.C.; Colman, P.M. Protein Sci. 1995, 4, 1081
4. 4. Bamford, M.J.; Castro-Pichel, J.; Patel, B.; Storer, R.; Weir, N.G. J Chem Soc Perkin Trans I. 1995, 1181.
5. 5. Sollis, S.L.; Howes, P.D.; Smith, P.W.; Cherry, P.C.; Bethell, R.C. Bioorg Med Chem Lett. 1996, 6, 1805.
6. 6. A library containing 80 amides was prepared which included compound 4k. Further details of this work will be reported in a full paper.
7. 7. Woods, J.M.; Bethell, R.C.; Coates, J.A.V.; Healy, N.; Hiscox, S.A.; Pearson, B.A.; Ryan, M.; Ticehurst, J.; Tilling, J.; Walcott, S.M.; Penn, C.R. Antimicrobial Agents Chemother. 1993, 37, 1473
8. 50's from different experiments differed by a factor of no more than 2.
9. 9. Throughout the text the amino acid residues are numbered for influenza A sialidase
10. 10. Molecular dynamics simulations were performed using a molecular dynamics/energy minimisation conformational searching protocol which incorporates multiple randomisation steps (Taylor, N.R.: von Itzstein, M. J. Med. Chem. 1994, 37, 616). The CVFF forcefield within the software package Discover was used (Biosym Technologies Inc., San Diego, USA). Fifteen energy minimised conformations were generated for each complex, and each simulation involved 70 ps of constrained molecular dynamics at 350 deg. K.