In-silico screening and molecular dynamics simulation of purpuride from Talaromyces marneffei strain SA2a: A potential inhibitor of Burkholderia virulence and drug resistance proteins

Abstract

Burkholderia are Gram-negative bacteria that belong to two complexes, the Burkholderia pseudomallei complex and Burkholderia cepacia complex. These bacteria possess virulence and multidrug resistance properties that can prolong melioidosis and necrotizing pneumonia in infected patients. This study aims to investigate the activities of Purpuride on Burkholderia virulence and multidrug resistance proteins (BVDRP) using in silico molecular docking. Ligand and protein structures were obtained from PubChem and Research Collaboratory for Structural Bioinformatics database. Toxicity and pharmacokinetic properties of Purpuride and reference ligand 1-(1-naphthylmethyl)piperazine and Luteolin were predicted with ADMETlab and admetSAR online tools. Molecular docking was performed using CB-Dock2 online server, and interaction between the ligands and BVDRP was visualized with BIOVIA Discovery Studio Visualizer. Structural stability and interaction dynamics of the protein–ligand complexes were performed using GROMACS 2023.4 with the CHARMM36-jul2021 force field. Purpuride showed low toxicity and favourable pharmacokinetic properties. Purpuride demonstrated a good binding affinity -8.5 kcal·mol⁻¹ with multidrug efflux transporter BpeB protein (7WLS), -7.5 kcal·mol⁻¹ with BceF Tyrosine Kinase Domain protein (6Z0P), and formed strong interactions with amino acid residues compared to reference inhibitors. Structural stability analyses, including RMSD, RMSF, H-bond, and radius of gyration, indicated that Purpuride is stable with 7WLS, while Luteolin is the stable reference for 6Z0P, exhibiting minimal fluctuations and a compact conformation. The in-silico and MD simulations study suggests that Purpuride is a better inhibitor of 7WLS but a weak target for 6Z0P. Purpuride could serve as an alternative agent against drug resistance in Burkholderia pseudomallei infection.