A STRATEGY FOR THEORETICAL BINDING CONSTANT, K-I, CALCULATIONS FOR NEURAMINIDASE AROMATIC INHIBITORS DESIGNED ON THE BASIS OF THE ACTIVE-SITE STRUCTURE OF INFLUENZA-VIRUS NEURAMINIDASE

Neuraminidase (NA) is one of the two major surface antigens of influen za virus. It plays an indispensable role in the release and spread of progeny virus particles during infection. NA inhibitors reduce virus i nfection in animals. To improve the clinical efficacy of NA inhibitors , we have begun the design of noncarbohydrate inhibitors based on the active site structure of NA. The approach is an iterative process of l igand modeling and electrostatic calculations followed by chemical syn thesis of compounds, biological testing, and NA-inhibitor complex stru cture determination by X-ray crystallography, A strategy has been deve loped to calculate K-i for newly designed inhibitors. The calculations using the DelPhi program were performed for carbohydrate inhibitors a nd three preliminary benzoic acid inhibitors of neuraminidase (BANA) t hat have been synthesized and shown to bind to the active site of NA i n the crystal structure. The calculated K(i)s of these inhibitors have an enlightening agreement with their in vitro biological activities. This demonstrates that the calculations produce informative results on the affinity of modeled inhibitors. GRID maps were also calculated an d several pockets were identified for accepting possible new ligands. The calculated K(i)s for newly designed ligands suggest that these pot ential compounds will have high inhibitory activities. (C) 1995 Wiley- Liss, Inc.