Influenza structure-based inhibitor design

A fine example of structure-based drug design has been reported for the design of an influenza virus neuraminidase inhibitor (see Scheme 11). Neuraminidase is an enzyme expressed on the surface of influenza virions and it is thought to be important for the successful release of progeny. Inhibition of... 

Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El Kattan Y, Lin TH, Hutchison TL, Elliott AJ, Parker CD, Ananth SL, Horn LL, Laver GW, Montgomery JA. BCX-1812 (RWJ-270201) discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J Med Chem 2000 43 3482-3486. 

Chand P, Babu YS, Bantia S, Chu NM, Cole LB, Kotian PL, Laver WG, Montgomery JA, Pathak VP, Petty SL, Shrout DP, Walsh DA, Walsh GW. Design and synthesis of benzoic acid derivatives as influenza neuraminidase inhibitors using structure-based drug design. J Med Chem 1997 40 4030-4052. 

Stoll V, Stewart KD, Mating CJ, Muchmore S, Giranda V, Gu Y-GY, Wang G, Chen Y, Sun M, Zhao C, Kennedy AL, Madigan DL, Xu Y, Saldivar A, Kati W, Laver G, Sowin T, Sham HL, Greer J, Kempf D (2003) Influenza neuraminidase inhibitors structure-based design of a novel inhibitor series. Biochemistry 42 718-727... 

X-ray crystal structures of a-Neu5Ac and 11 in complex with influenza virus sialidases in the 1980s and early 1990s led to the opportunity for structure-based design and development of influenza virus sialidase inhibitors [66, 85],... 

T., Sham, H.L., Greer, J., and Kempf, D. (2003) Influenza neuraminidase inhibitors structure-based design of a novel inhibitor series. Biochemistry, 42, 718-727. 

Roy and coworkers have designed inhibitors of influenza virus hemagglutinin based on several different dendrimer backbones [109,110]. Using solid phase syntheses, they generated sialic acid-displaying dendrimers based on a poly-L-lysine core structure (O Fig. 17) as ligands for influenza virus hemagglutinin. These dendrimers, which bear 2, 4, 8, or 16 pendant sialic... 

The computer-aided design of potent inhibitors of influenza virus sialidase based on a crystal structure of the enzyme has been described. A combination of manual molecular graphics analysis and the de novo ligand design tool GRID was used to identify modifications to the... 

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