Computational Discovery of BMS-986205 as a Resistance-Proof Inhibitor for the Nipah Virus Polymerase

Nipah virus (NiV) represents a catastrophic public health risk to the Indian subcontinent, as evidenced by recurring outbreaks in Kerala (2018, 2021, 2023) where case fatality rates reached as high as 70-90%. There are currently no clinically approved therapeutics or vaccines specifically for NiV. A major hurdle in the drug development pipeline is the high mutation rate of RNA viruses, which allows them to rapidly evolve resistance against site-specific inhibitors. This research project utilizes a multi-layered computational strategy to identify a small-molecule inhibitor capable of targeting the viral polymerase while maintaining efficacy against the predicted high-probability W730A resistance mutation. Through a first-principles assessment of the viral polymerase structure (PDB: 9KNZ), I established a design constraint called Allosteric Independence. This requires any lead candidate to bind in a pocket that is geometrically distinct from the mutation site W730, thereby preventing steric or electronic disruption upon mutation. After screening a library of 50 high-potential candidates using a rigid-receptor docking protocol, I identified BMS-986205 (Linrodostat), an investigational IDO1 inhibitor, as a superior lead. BMS-986205 demonstrated a binding affinity of -7.17 kcal/mol against the wild-type polymerase and a paradoxical increase to -7.29 kcal/mol against the W730A mutant. Geometric analysis confirmed a physical separation of 6.28 Å from the mutation site. Given its current status in global Phase 3 clinical trials for oncology, BMS-986205 is a primary candidate for rapid drug repurposing to secure India’s population against future outbreaks.