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In silico screening and molecular dynamics analysis of natural DHPS enzyme inhibitors targeting Acinetobacter baumannii

Summary

Researchers used computer modeling to find natural compounds from plants and mushrooms that can inhibit a key bacterial enzyme (DHPS) in dangerous antibiotic-resistant bacteria called Acinetobacter baumannii. They tested thousands of natural molecules and identified two promising candidates that bind strongly to this enzyme and prevent bacteria from producing folic acid, which they need to survive. The study suggests these natural compounds could potentially be developed into new antibiotics to fight infections caused by drug-resistant bacteria.

Background

Acinetobacter baumannii is a multi-drug resistant pathogen causing serious infections with increasing antimicrobial resistance. The dihydropteroate synthase (DHPS) enzyme is essential for bacterial folic acid synthesis and represents a viable drug target. Natural compounds from medicinal plants and fungi offer potential antimicrobial agents with fewer side effects than synthetic drugs.

Objective

To screen natural ligands from medicinal plants and Agaricus fungi against the DHPS enzyme of A. baumannii using virtual screening and molecular dynamics simulations. To identify and validate natural compound inhibitors of DHPS through computational and binding affinity analysis.

Results

Two ligands (MSID_000725 and CID_291096) demonstrated favorable binding affinities of -7.06 and -7.42 kcal/mol respectively through AutoDock analysis. MM/PBSA binding free energy calculations showed DHPS-MSID_000725 complex with -25.18 kcal/mol and DHPS-CID_291096 with -4.90 kcal/mol. Molecular dynamics analysis confirmed stable interactions through RMSD, RMSF, Rg, SASA, and principal component analysis parameters.

Conclusion

MSID_000725 and CID_291096 are potential natural inhibitors of DHPS enzyme in A. baumannii with spontaneous binding and stability. MSID_000725 demonstrates superior binding affinity compared to the FDA-approved drug Clofazimine reference compound. Further experimental and clinical validation is necessary before these compounds can be considered for drug development.
  • Published in:Scientific Reports,
  • Study Type:Computational Drug Discovery Study,
  • Source: PMID: 40044750, DOI: 10.1038/s41598-025-90946-9
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