COMBINE 3D-QSAR Analysis of Influenza Neuraminidase Inhibitors

Ting Wang and Rebecca C. Wade

European Molecular Biology Laboratory, Meyerhofstrasse 1, 69012 Heidelberg, Germany

Neuraminidase (NA) is a surface glycoprotein of influenza viruses which cleaves terminal sialic acids from glycoproteins and glycolipids and is critical for viral replication. The active site of neuraminidase[1,2] is conserved in all type A and B influenza viruses, making it an excellent target for anti-influenza drug design. Indeed, neuraminidase inhibitors have recently become available in the clinic for treatment of influenza . We describe the use of structures of protein-inhibitor complexes to derive quantitative structure-activity relationships (QSARs) which should aid understanding of the mechanism of inhibition and the discovery of new inhibitors. Crystal structures of 30 NA-inhibitor complexes as well as 12 complexes with inhibitors docked by the AUTODOCK program[3] were used to build a 3D-QSAR model by COMparative BINding Energy (COMBINE) analysis[4]. The proteins included subtype N2, subtype N9 and the N9 mutant of type A NA. The inhibitors [5-6] included sialic acid and benzoic acid analogues. A predictive QSAR model was obtained and protein residues and bound water molecules important for inhibitor activity were highlighted in the QSAR model. In addition, based on the COMBINE analysis, a 4-point pharmacophore was proposed and was used to search for matching compounds in 3D structural databases by the 3DFS program [7]. Some hits with novel structures were obtained.


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In ``Rational Approaches to Drug Design: 13th European Symposium on Quantitative Structure-Activity Relationships''
Eds. Holtje, H-D., Sippl,W. (2001), Prous Science S.A., Barcelona, pp78-82.