Accelerated Discovery of Potent Fusion Inhibitors for Respiratory Syncytial Virus.

A series of five benzimidazole-based compounds were identified by way of a machine-learning algorithm as potentially potent inhibitors of the respiratory syncytial virus (RSV) fusion protein. These compounds were synthesized and compound 2 in particular exhibited excellent in vitro potency with an EC50 value of 5 nM. This new scaffold was then further refined using structure-based design to incorporate a halogen bonding interaction with Thr397, ultimately leading to the identification of compound 44, which exhibited a 10-fold improvement in activity with an EC50 value of 0.5 nM.