Recursive dynamics of GspE through machine learning enabled identification of inhibitors

Area of Science:

• Microbiology
• Computational Biology
• Drug Discovery

Background:

• Achromobacter xylosoxidans is an opportunistic Gram-negative pathogen, frequently causing infections in immunocompromised individuals, particularly those with cystic fibrosis.
• The Type II secretion system (T2SS) is a critical virulence factor in A. xylosoxidans, with the ATPase GspE being essential for its function.
• The increasing antibiotic resistance of A. xylosoxidans necessitates the development of novel therapeutic strategies targeting its virulence mechanisms.

Purpose of the Study:

• To computationally identify and characterize potential inhibitors of the GspE ATPase from A. xylosoxidans.
• To leverage machine learning and molecular dynamics simulations to screen drug libraries and validate lead compounds.

Main Methods:

• Machine learning (Random Forest algorithm) was employed to screen a large dataset of antibacterial compounds against GspE.
• Promising candidates underwent molecular docking and extensive molecular dynamics (MD) simulations.
• Post-simulation analyses included trajectory analysis, atom contacts, SASA, hydrogen bonding, RDF, binding free energy calculations, PCA, and AFD analysis.

Main Results:

• The compound Asinex-BAS00263070-28551 emerged as the top-ranked inhibitor, demonstrating significant binding affinity to the GspE ATPase.
• MD simulations revealed that Asinex-BAS00263070-28551 stabilizes the GspE complex through key hydrogen bond interactions with the Walker A motif.
• The identified interactions suggest a mechanism of inhibiting GspE's ATPase activity and consequently disrupting the T2SS.

Conclusions:

• Asinex-BAS00263070-28551 represents a promising drug candidate for targeting GspE in A. xylosoxidans.
• This computational approach provides a strong foundation for developing new treatments against this challenging pathogen.
• Further in vitro and in vivo experimental validation is warranted to confirm the therapeutic potential of this compound.