Hybrid Computational Framework Integrating Ensemble Learning, Molecular Docking, and Dynamics for Predicting Antimalarial Efficacy of Malaria Box Compounds

The emergence of drug-resistant strains of Plasmodium falciparum continues to challenge global malaria control efforts, underscoring the urgent need for novel therapeutic strategies. In this study, we present an integrative computational framework that combines ensemble machine learning, molecular docking, and molecular dynamics simulations to predict and characterize the antimalarial activity of compounds from the Malaria Box database. Initially, topographical and quantum mechanical descriptors were used to construct regression models for predicting pEC₅₀ values, but due to the limited predictive performance in the global regression, a classification strategy was adopted, categorizing compounds into “active” and “very active” classes. The best ensemble classifier achieved robust performance (Acc₁₀-fold = 0.738, Acc_ext = 0.675), with good sensitivity and specificity over individual models. Subsequent regression modeling within each class yielded high predictive accuracy, with ensemble models reaching Q²10-fold values of 0.810 and 0.793 for the very active and active classes, respectively. To explore potential mechanisms of action, molecular docking was performed against P. falciparum Cytochrome B, revealing strong binding affinities for most compounds, particularly those forming π–π stacking and hydrogen bonds with Glu272. Molecular dynamics simulations over 200 ns confirmed the stability of several ligand–protein complexes, including unexpected behavior from compound M31, which demonstrated stable binding despite poor docking scores, suggesting a possible competitive inhibition mechanism. Binding free energy calculations further validated these findings, highlighting several promising candidates for future experimental evaluation. This integrative approach offers a powerful platform for accelerating antimalarial drug discovery by combining predictive modeling with mechanistic insights.