Computer-assisted Assessment of Bioactive Compounds from Endophytic Fungi Against Type III Transcription Regulator (HrpR) of Pseudomonas synringae pv

Abstract

Pseudomonas syringae pv. tomato (Pst) is a well-studied bacterial pathogen affecting tomato crops globally, leading to significant yield and economic losses. Typical control measures, including copper-based bactericides, face increasing limitations due to the emergence of resistant strains. In order curb this challenges, In silico analysis were employed to evaluate secondary metabolites from endophytic fungi as potential inhibitors of the HrpR protein, a key regulator of the Type III secretion system in Pst. A total of 100 fungal-derived compounds were screened using molecular docking, ADMET profiling, and molecular dynamics (MD) simulations. Six major hits with strong binding affinities were identified, with Asperthrins A emerging as the most promising lead. Asperthrins A exhibited best pharmacokinetic properties, including low toxicity (LD₅₀ = 3.04), low hERG and DILI. MD simulations confirmed its stable binding and structural compactness within the HrpR active site over a 200 ns trajectory. Compared to other candidates such as Kadhenrischinins F and Diaporthichalasins E, Asperthrins A consistently outperformed in key pharmacological metrics. These findings underscore the value of endophytic fungi as sources of bioactive compounds and demonstrate the power of structure-based drug discovery in identifying environmentally safe, plant-compatible antimicrobial agents. This study provides a foundational step toward developing bio-rational alternatives to synthetic bactericides, supporting sustainable plant health management.