STOLL VS, MCDANIEL K, ZHAO C, MADIGAN D, SUN MH, KENNEDY A, KRUEGER AC, HERRIN TR, FLOSI WJ, GRAMPOVNIK DJ, DEGOEY DA, CHEN HJ, YEUNG CM, MOHAMMADI F, MARING C, KLEIN LL, MONTGOMERY DA, SALDIVAR AC, KATI WM, STEWART K, LAVER WG, KEMPF DJ, KOHLBRENNER WE; Interscience Conference on Antimicrobial Agents and Chemotherapy.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 221.
Abbott Lab., Abbott Park, IL
Neuraminidase is the target of anti-influenza drugs because of its pivotal role in the viral life cycle and the conserved nature of the neuraminidase active site. We have defined 5 subsites within the active site: Site 1 is comprised of 3 arginine residues and has a high affinity for carboxylate or phosphonate anionic groups. Site 2 is mainly an anionic pocket with a high affinity for polar or cationic groups within inhibitors or substrates. Site 3 is termed the amide recognition site with hydrophobic and hydrogen bonding groups complementary to acetamido or methylsulfonamide groups. Previous work identified a fourth region, which we further divide into site 4, comprised of Arg226, Ile224 and Ala248, and site 5, which consists primarily of Glu278 in multiple conformations. This poster will compare and contrast the site 1-5 binding modes of known neuraminidase inhibitors GG167, BCX1812, and GS4071 as determined by protein x-ray crystallographic studies with both Type A and B enzymes. In addition, a previously unknown hydrophobic portion of site 2 is described along with a novel series of inhibitors that exploit this novel pocket. Three-dimensional crystallographic studies of a variety of inhibitors will be described and compared with the three inhibitors listed above. Companion posters will discuss antiviral and pharmacokinetic data on the compounds presented.KEYWORDS: Inhibitor; Neuraminidase; Pyrrolidine
Publication Types:
Keywords:
- Antiviral Agents
- Binding Sites
- Crystallization
- Cyclopentanes
- Hydrogen Bonding
- Influenza Vaccines
- Molecular Conformation
- Neuraminidase
- Sialic Acids
- X-Rays
- Zanamivir
- peramivir
- radiography
Other ID:
UI: 102248157
From Meeting Abstracts