National Biomedical Computation Resource, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
Mediating the release of daughter viral particles from host cells, neuraminidase is essential for the spread of influenza infections and thus a key target for antiviral drug development. This study presents a novel scaffold-based, fragment-growing method to identify molecular scaffolds for neuraminidase inhibitor design. The receptor structure of a Group 1 neuraminidase mutant isolated from a Tamiflu-resistant strain of Influenza A was derived from PDB 3CKZ. An initial set of low-affinity geometric scaffolds was inputted into AutoGrow, the fragment-growing application used in this study. AutoGrow randomly mutates an initial input molecule with substituents from a fragment library. Using AutoDock Vina as a scoring function, mutations leading to increased binding affinity are preserved for the next generation and the cycle of mutation and selection continues until an effective inhibitor eventually evolves.
After eight cycles, all scaffolds increased in binding affinity; however, some clearly showed more successful evolutionary trajectories and evolved into ligands of significantly higher binding affinity. The core scaffold of NSC 109836, a known hit, had an initial binding affinity of -7.4 kcal/mol and evolved to an average final binding affinity of -10.13 ± 0.29 kcal/mol. The adamantane scaffold, a novel molecular geometry not currently used by any known neuraminidase inhibitors, initially bound with mediocre affinity: -5.3 kcal/mol. However, after eight generations, adamantane acquired an average affinity of -10.67 ± 0.21 kcal/mol, surpassing known hits such as NSC 109836. Adamantane was thus identified by this study as a novel, potential scaffold for neuraminidase inhibitor development. Analyzing the substituents of adamantane derivatives revealed consistent trends: top endpoint molecules of parallel, independent evolutions all acquired a sulfate-containing branch, as well as an alcoholic branch exactly 4 bonds away. For validation, ligands derived from the Zanamivir scaffold had nearly identical fragment attachment sites as the original Zanamivir ligand. Visualizing the binding modes of the spectrum of evolved compounds in MOE yielded a list of neuraminidase residues most accessible to binding. Residues were ranked based on how many times they were targeted by an endpoint ligand. Top-scoring residues not only included major residues targeted by current inhibitors, but also suggested new, potentially bindable residues: Tyr 406, Arg 371, Tyr 347, Arg 292, Ser 179, and Arg 118.
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