Virtual screening and molecular dynamic simulations of

Dissimilatory sulfite reductase (DSR) plays a crucial role in the metabolism of sulfate-reducing bacteria (SRB), which contribute to environmental hazards such as biocorrosion and sulfide pollution. The search for effective DSR inhibitors has been challenging due to the difficulty in culturing strict anaerobes. In this study, we employed molecular docking and 100 ns molecular dynamics (MD) simulations to screen 248 microbially-derived compounds for their potential as DSR inhibitors. Based on docking scores, nine hit compounds were identified, with dehydrocitreaglycon A exhibiting the highest binding affinity (-9.4 kcal/mol), followed by citreamicin theta A and etamycin. Hydrogen bond interaction analysis revealed that key active site residues, including Arg83, Arg101, and Lys215, played significant roles in ligand binding. MD simulations revealed varying stability among the DSR-compound complexes, with arisugacin A demonstrating the highest stability and minimal fluctuations, while antimycin A1 and peniciadametizine A showed the highest instability. The principal component analysis (PCA) indicated greater conformational flexibility in complexes with antimycin A1, etamycin, citreamicin theta A, and terretonin G. Binding free energy calculations confirmed that dehydrocitreaglycon A (-112.13 kJ/mol) and strobilurin (-107.66 kJ/mol) had the most favorable interactions with DSR. Furthermore, an in silico environmental toxicity assessment indicated that some compounds, such as salmochelin sx, posed higher toxicity risks, whereas others, like dehydrocitreaglycon A, showed lower environmental impact. Overall, our findings highlight strobilurin, arisugacin A, and dehydrocitreaglycon A as promising DSR inhibitors, warranting further investigation for potential applications in SRB control. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00367-9.