Machine learning-driven drug repurposing and computational validation for Nipah virus

The recurring Nipah virus outbreaks and the lack of effective antiviral therapies, emphasize the urgent need for effective therapeutic interventions. Given the sporadic and unpredictable nature of NiV outbreaks, drug repurposing offers a time-efficient alternative to the development of novel antivirals. In this study, we leveraged machine learning (ML) techniques to accelerate the process of identifying potential therapeutic candidates. Several supervised ML models such as Support Vector Machines, Random Forest, Logistic Regression, Decision Tree, k-Nearest Neighbors, Artificial Neural Networks, and Ridge Classifier were implemented using publicly available NiV inhibitor datasets (viz. Anti-Nipah, NVIK, PubChem) as well as literature review (n = 211 compounds). Among these, the Random Forest model demonstrated highest predictive performance, achieving high accuracy on both training (95%) and testing (86%) datasets. The optimized model was subsequently applied to screen FDA-approved, preclinical, clinical, and antiviral drug libraries (comprising 9021 compounds) to identify potential anti-NiV candidates. The shortlisted compounds underwent further validation through molecular docking to evaluate binding affinity and molecular dynamics simulations to assess structural stability and interactions with key viral targets, including the glycoprotein and RNA-dependent RNA polymerase (RdRp). Based on docking scores and molecular dynamics stability, we identified three and five promising candidates: 2,3,4,5,6-Pentagalloylglucose, Echinacoside, Parishin A, and Neohesperidin dihydrochalcone, Naringin dihydrochalcone, Diosmin, Orientin, Amikacin, against the glycoprotein and RdRp respectively. This integrative approach, combining ML, drug repurposing, and computational validation, aims to expedite the discovery of effective therapeutic agents against the Nipah virus and strengthen preparedness for future outbreaks.