Designed LL-37 derived peptides P3, A5ζ, and A4η show strong KatG binding affinity in computational models

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis, exacerbated by the emergence of drug-resistant strains. Current treatments are often ineffective against multidrug-resistant tuberculosis (MDR-TB), necessitating novel therapeutic strategies. The Mtb enzyme catalase-peroxidase G (KatG) is a critical resistance determinant, essential for activating isoniazid and protecting bacteria from oxidative stress. Mutations in KatG are a primary mechanism of isoniazid resistance, making it a crucial target for new antimicrobial peptides (AMPs).

Researchers designed a library of 15 novel antimicrobial peptides by rationally modifying the host-defense peptide LL-37 to enhance efficacy against M. tuberculosis. These peptides were categorized into three classes (Class I, II, III). Peptide structures were predicted and then subjected to molecular docking simulations against the KatG enzyme to identify top candidates based on binding affinity. The three top-performing peptides, P3, A5ζ, and A4η, were then further analyzed using molecular dynamic (MD) simulation for 100 ns to assess their conformational stability within the KatG-peptide complexes. Additionally, an in silico safety assessment was performed to evaluate their physicochemical and ADME properties.

Molecular docking simulations identified three top peptides with strong binding affinities to the KatG active site residues. Peptide P3 exhibited the highest binding score of -235.28, followed by A4η at -233.81, and A5ζ at -229.42. These scores indicate robust interactions with the target enzyme. Molecular dynamic (MD) simulation over 100 ns revealed distinct stability profiles for the protein-peptide complexes, with P3 demonstrating exceptional conformational stability, suggesting a highly stable interaction with KatG. Additionally, in silico safety assessments confirmed that the designed peptides possessed non-toxic, non-allergenic, and favorable physicochemical and ADME (absorption, distribution, metabolism, and excretion) properties. This suggests a promising safety profile for potential therapeutic development.

The computationally designed peptides P3, A5ζ, and A4η showed strong binding affinity to KatG, with P3 achieving a binding score of -235.28, indicating potential to disrupt mycobacterial enzymatic functions.