Inhibitory efficacy and binding mode prediction of natural compounds against pathogenic factors of Alternaria solani: insights from alpha-fold, molecular simulations, and post-simulation analyses

The necrotic fungal pathogen Alternaria solani is the source of early blight disease, which poses a significant risk to crop productivity worldwide and mostly affects extensively grown commodities like tomatoes and potatoes. The need for sustainable substitutes for traditional chemical fungicides has increased due to the ongoing revelation of fungicide resistance issues. That is the reason, in this study, we focus on the inhibitory potential of natural compounds against two critically important effector proteins, AsCEP112 and AsCEP50 , directly associated with A. solani infection. A comprehensive and specific library of 608 natural compounds with known antifungal properties was evaluated using the most relevant advanced computational approaches. While BR -xanthone A exhibits satisfying binding scores to both selected proteins, the other two compounds, Allicin and Alpha-mangostin, also demonstrate considerable binding affinities to AsCEP50 and AsCEP112 , respectively, in molecular docking studies compared to reference fungicides (Strobilurin and Azoxystrobin). Furthermore, calculating parameters such as RMSD, RMSF, Rg, SASA, and hydrogen bonds for proper assessment of stability, high-throughput molecular dynamics (MD) simulations were conducted. Post simulation analyses, including MM-PBSA, PCA, FEL, and PDF, further validated the integrity of the ligand-protein complexes and revealed probable conformational changes. Moreover, BR xanthone A exhibited excellent bioactivity scores and fungicide-likeness, outperforming the reference compounds. Finally chosen compound, BR-xanthone A, offering a glimpse of hope for developing natural compound-based fungicides by specifically targeting fungal pathogenic factors. Though for confirmation, it needs a rigorous field trial. This research paves the way for developing future natural compound-based fungus control agents that could be an effective alternative to chemical fungicides and probably mitigate the issues of chemical fungicide resistance.