Innovative Multistage ML-QSAR Models for Malaria: From Data to Discovery.

Malaria presents a significant challenge to global public health, with around 247 million cases estimated to occur annually worldwide. The growing resistance of parasites to existing therapies underscores the urgent need for new and innovative antimalarial drugs. This study leveraged artificial intelligence (AI) to tackle this complex challenge. We developed multistage Machine Learning Quantitative Structure-Activity Relationship (ML-QSAR) models to effectively analyze large datasets and predict the efficacy of chemical compounds against multiple life cycle stages of parasites. We then selected 16 compounds for experimental evaluation, six of which showed at least dual-stage inhibitory activity and one inhibited all life cycle stages tested. Moreover, explainable AI (XAI) analysis provided insights into critical molecular features influencing model predictions, thereby enhancing our understanding of compound interactions. This study not only empowers the development of advanced predictive AI models but also accelerates the identification and optimization of potential antiplasmodial compounds.