Structure-based identification of small molecule inhibitors targeting trigger factor and peptidyl prolyl cis/trans isomerase B (PpiB) of Bacillus anthracis Sterne: Towards new therapeutic interventions against anthrax

Anthrax, caused by Bacillus anthracis, remains a critical zoonotic threat, with treatment efficacy increasingly compromised by advanced infection progression and rising antibiotic resistance. This study leverages integrative computational strategies to identify and characterize novel therapeutic targets among previously uncharacterized molecular chaperones-Trigger Factor (BASTig) and peptidyl-prolyl cis-trans isomerase B (BASPpiB)-from B. anthracis Sterne. Structural elucidation using homology modelling and AlphaFold revealed distinctive architectures for BASTig (425 residues) and BASPpiB (145 residues). High-throughput virtual screening of diverse chemical libraries pinpointed compounds 51002 and 50423 as promising inhibitors, with strong binding affinities of −52.58 and −66.4 kcal/mol, respectively. ADME profiling confirmed favourable drug-like properties, and molecular dynamics simulations demonstrated stable protein–ligand interactions. Quantum mechanical calculations further supported the electronic complementarity and thermodynamic stability of these complexes. Electrostatic surface potential (ESP) analysis revealed that compound 51002 features predominantly positive charge distributions, favouring interactions with acidic residues in BASTig, while compound 50423 displays heterogeneous electrostatic regions, enabling adaptive binding to BASPpiB's dynamic pocket. Toxicity predictions indicated acceptable safety profiles for both leads. Immunogenicity assessment showed differential antigenic potential (BASPpiB: 100 %, BASTig: 66 %). Epitope mapping with ABCpred identified multiple high-scoring, spatially distributed B-cell epitopes in both proteins, with substantial concordance between predictive algorithms. These results highlight the therapeutic promise of targeting molecular chaperones in B. anthracis and provide a foundation for both small-molecule drug discovery and rational immunogen design, addressing urgent needs in anthrax intervention and antimicrobial resistance.