Current drug discovery technologies · 2026
Targeting Biofilm Formation in Acinetobacter baumannii: In Silico Discovery of Novel Candidate Inhibitors for Acyl-Homoserine Lactone Synthase.
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Singh Tejveer, Singh Rashmi Prabha, Jain Monika, Muthukumaran Jayaraman, Singh Amit Kumar
Аннотация
INTRODUCTION: Acinetobacter baumannii, a Gram-negative member of the ESKAPE pathogens, has emerged as a pivotal cause of multidrug-resistant hospital-acquired or nosocomial infections worldwide. Its ability to regulate virulence and biofilm formation through quorum sensing (QS) significantly contributes to its virulence and pathogenicity. Acyl-homoserine lactone synthase (AHLS) from the A. baumannii AYE strain plays a key role in the QS pathway and represents a promising druggable target for the development of anti-bacterial strategies.
METHODOLOGY: A homology-modeled three-dimensional structure of AHLS (AYE strain) was predicted, optimized, and validated. High-throughput virtual screening of 975 natural antimicrobial compounds was performed, followed by Lipinski's and ADMET profiling to assess drug-likeness and safety. Promising drug candidates were further evaluated using 100ns molecular dynamics (MD) simulations to identify putative AHLS inhibitors.
RESULTS: MM/PBSA based binding free energy calculations revealed favorable interactions for CID_291096 (-14.74 ± 2.20 kcal/mol), CID_155586 (-15.26 ± 2.27 kcal/mol), and MSID_001127 (-28.44 ± 3.32 kcal/mol). Among these, MSID_001127 (Lovastatin) demonstrated superior structural stability and sustained intermolecular non-covalent interactions throughout the 100ns MD simulation. Structural stability was further supported by RMSD, RMSF, Rg, SASA, PCA, and hydrogen-bonding analyses.
DISCUSSION: Through virtual screening, three phytochemical lead compounds targeting AHLs with high negative binding free energies were identified. Stable protein-ligand interactions and favourable binding energetics were identified by molecular docking, 100 ns molecular dynamics simulations, and MM/PBSA analyses. Based on the results, ligand MSID_001127 was the most promising lead candidate compared with cipargamin. However, additional experimental validation is required to verify its therapeutic potential and biological activity.
CONCLUSION: These findings suggest that Lovastatin may be a promising drug candidate for AHLS targeting the QS pathway of A. baumannii. The results warrant further experimental validation to explore its potential as an anti-bacterial therapeutic agent.
METHODOLOGY: A homology-modeled three-dimensional structure of AHLS (AYE strain) was predicted, optimized, and validated. High-throughput virtual screening of 975 natural antimicrobial compounds was performed, followed by Lipinski's and ADMET profiling to assess drug-likeness and safety. Promising drug candidates were further evaluated using 100ns molecular dynamics (MD) simulations to identify putative AHLS inhibitors.
RESULTS: MM/PBSA based binding free energy calculations revealed favorable interactions for CID_291096 (-14.74 ± 2.20 kcal/mol), CID_155586 (-15.26 ± 2.27 kcal/mol), and MSID_001127 (-28.44 ± 3.32 kcal/mol). Among these, MSID_001127 (Lovastatin) demonstrated superior structural stability and sustained intermolecular non-covalent interactions throughout the 100ns MD simulation. Structural stability was further supported by RMSD, RMSF, Rg, SASA, PCA, and hydrogen-bonding analyses.
DISCUSSION: Through virtual screening, three phytochemical lead compounds targeting AHLs with high negative binding free energies were identified. Stable protein-ligand interactions and favourable binding energetics were identified by molecular docking, 100 ns molecular dynamics simulations, and MM/PBSA analyses. Based on the results, ligand MSID_001127 was the most promising lead candidate compared with cipargamin. However, additional experimental validation is required to verify its therapeutic potential and biological activity.
CONCLUSION: These findings suggest that Lovastatin may be a promising drug candidate for AHLS targeting the QS pathway of A. baumannii. The results warrant further experimental validation to explore its potential as an anti-bacterial therapeutic agent.