Design of oseltamivir analogs inhibiting neuraminidase of avian influenza virus H5N1

Abstract

Neuraminidase is an important target for design of antiviral agents in the prophylaxis and treatment of avian influenza virus infections. We have shown the applicability of computer-assisted combinatorial techniques in the design, focusing and in silico screening of a virtual library of analogs of oseltamivir (Tamiflu) with the goal to find potent inhibitors of influenza A neuraminidase N1 that fill the cavity found adjacent to the active site. Crystal structure of oseltamivir-N1 complex was used in the structure-based focusing and virtual screening of the designed library. A target-specific Piecewise Linear Potential type 1 scoring function fitted for a training set of 14 carbocyclic inhibitors and validated for three other inhibitors was used to select virtual hits with predicted inhibitory activities in the subnanomolar range. The results of this computational study are useful as a rational guide for synthetic and medicinal chemists who are developing new drugs against the avian influenza virus H5N1.