A novel compound to overcome influenza drug resistance in endonuclease inhibitors

Influenza is a seasonal respiratory illness that kills hundreds of thousands of people every year. Currently, neuraminidase inhibitors and endonuclease inhibitors are used in antiviral therapy. However, both drug types have encountered drug-resistant influenza strains in the human body. Fortunately, there is currently no resistance to endonuclease inhibitors in wild strains of influenza. We obtained the molecules with endonuclease inhibitor activity independent of the existing drug-resistant strains through computer-aided drug design, and we hope the obtained results can lay a theoretical foundation for the development of high-activity endonucleases. Combining a traditional fragment-based drug discovery approach with AI-directed fragment growth, we selected and designed a compound that achieved antiviral activity on drug-resistant strains by avoiding mutable residues and drug-resistant residues. We predicted the related properties using an ADMET model. Finally, we obtained a compound similar to baloxavir in terms of binding free energy but not affected by baloxavir resistance. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11030-023-10659-x.