Identification of Antimicrobial Peptides Against Helicobacter pylori Targeting the Essential Homeostatic Stress Regulator A (HsrA): An In Silico Approach
TL;DR
An in silico framework combining homology modelling, peptide screening, docking, MD simulations, and MM-GBSA analysis is developed to identify antimicrobial peptides targeting HsrA's DNA-binding domain, offering potential leads for peptide-based therapy against antibiotic-resistant H. pylori.
Abstract
Antibiotic-resistant H. pylori poses a growing global health threat, driving gastric diseases like peptic ulcers and adenocarcinoma. As conventional antibiotics become less effective, structure-based peptide design offers a targeted therapeutic alternative. HsrA is a vital transcription factor that regulates the expression of virulence genes, making it a highly important therapeutic target. The APD3 database was selected, approximately 3940 peptides were screened against HsrA using HDOCK, and the top five peptides were selected based on docking score. These HsrA–peptide complexes were then subjected to 200 ns molecular dynamics (MD) simulations using GROMACS 2024.1, followed by structural analysis and binding-energy estimation. Screening of 3,940 antibacterial peptides from the APD3 database using HDOCK identified five top-ranked candidates, with AP03442 and AP01521 exhibiting higher docking scores than the reference peptide TP4. Further, MD simulations confirmed stable and energetically favourable binding within the HsrA DNA-binding cleft, suggesting that these peptides may interfere with HsrA-mediated transcription and redox homeostasis, leading to bacterial death. Unlike previous studies, this study employed a full-length HsrA structure that includes the C-terminal DNA-binding region. We developed an in silico framework combining homology modelling, peptide screening, docking, MD simulations, and MM-GBSA analysis to identify antimicrobial peptides targeting HsrA's DNA-binding domain. Two lead peptides, AP03442 (GVF-24) and AP01521 (ChBac3.4), exhibited stronger binding affinity, stability, and interaction energies than the reference peptide TP4, suggesting their potential to inhibit HsrA by blocking DNA binding. This study identifies five antibacterial peptides targeting HsrA, offering potential leads for peptide-based therapy against antibiotic-resistant H. pylori.