New binary mixtures of fungicides against Macrophomina phaseolina: Machine learning-driven QSAR, read-across prediction, and molecular dynamics simulation

Quantitative Structure-Activity Relationship (QSAR) analysis greatly enhances the development and research of pesticides. This study employed Multiple Linear Regression (MLR), machine learning (ML), and read-across (RA) approaches to investigate the combined effects of binary mixtures of fungicides on Macrophomina phaseolina. Using the Fixed Ratio Ray Design (FRRD) method, 75 binary mixtures of six frequently used fungicides were generated, with many exhibiting additive interactions as indicated by the Concentration Addition (CA) and Independent Action (IA) models. The QSAR analysis revealed that Support Vector Regression (SVR) and Gaussian Process Regression (GPR) models were the most effective, outperforming the Least Squares Kernel (LSK), MLR, and RA methods. SVR achieved an outstanding R² of 0.95 and Q²_LMO of 0.81, whereas GPR demonstrated values of 0.93 and 0.81 for the same metrics. Internal and external validation confirmed the reliability and generalizability of these models, suggesting they could be applied to a wider array of data. Moreover, Molecular Dynamics (MD) simulations showed that the effects of the fungicides are linked to physiological mechanisms rather than intermolecular interactions within their formulations. This study establishes a robust framework for creating potent fungicide combinations that improve disease management efficacy while promoting environmental sustainability and reducing the chemical load to mitigate negative impacts.