Biologically active ligands for yersinia outer protein H (YopH): feature based pharmacophore screening, docking and...

Area of Science:

• Microbiology
• Structural Biology
• Drug Discovery

Background:

• Yersinia pestis causes plague by spreading through the lymphatic system and bloodstream.
• Yersinia outer protein H (YopH) is a key effector protein that impairs immune cells like lymphocytes and macrophages.
• YopH functions by dephosphorylating crucial tyrosine kinases and signal transduction molecules, leading to immune paralysis.

Purpose of the Study:

• To create a three-dimensional (3D) pharmacophore model for Yersinia outer protein H (YopH) inhibitors.
• To identify essential structural features contributing to YopH inhibitory activity.
• To facilitate the design of novel antitoxin compounds against Yersinia pestis.

Main Methods:

• A ligand-based pharmacophore study was conducted using 60 biologically active YopH inhibitors.
• Database screening identified novel compounds based on the pharmacophore model.
• In silico methods including docking, ADME property prediction, binding energy calculation, and molecular dynamics simulations (RMSD, RMSF) were employed for validation.

Main Results:

• The pharmacophore model revealed that two acceptor, one hydrophobic, and two aromatic features are critical for YopH inhibition.
• Screening and subsequent analyses identified four potential YopH inhibitors: ASN03270114, Mol_252138, Mol_31073, and ZINC04237078.
• Molecular dynamics simulations confirmed the stability and binding characteristics of the identified compounds.

Conclusions:

• The developed 3D pharmacophore model effectively captures essential features for YopH inhibition.
• The identified compounds show promise as potential inhibitors of Yersinia pestis YopH.
• This study provides a foundation for designing new antitoxin therapies against plague.