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Abstract <p><i>Tuberculosis</i> (TB) continues to pose a serious global health threat, particularly due to the emergence of drug-resistant strains that compromise current treatment regimens. The Antigen 85 (Ag85) complex, especially the Ag85C isoform, is a key virulence factor in <i>Mycobacterium tuberculosis</i> and a promising target for therapeutic intervention. We employed an integrated computational strategy to identify and characterize novel inhibitors targeting the Ag85C protein (PDB ID: 1DQY). Ligands were assessed for their drug-likeness and pharmacokinetics properties using SwissADME and PreADMET platforms. Molecular docking was performed using AutoDock Vina, followed by 200 ns molecular dynamics (MD) simulations with GROMACS and the AMBER99SB force field. MM/PBSA analysis quantified binding free energies and interaction mechanisms. Among screened compounds, Carnosic acid (Csa) and dihydrocurcumenone (Dic) were identified as lead inhibitors with binding energies of -7.95 and − 7.19&#xa0;kcal/mol, respectively. Both exhibited high gastrointestinal absorption (&gt; 92%) and favorable oral bioavailability. MD simulations confirmed the stability of ligand-protein complexes, with Root Mean Square Deviation (RMSD) values of 0.190 ± 0.014&#xa0;nm for Csa and 0.154 ± 0.008&#xa0;nm for Dic. MM/PBSA calculations revealed stronger binding affinity for Csa (-98.718 ± 17.087&#xa0;kJ/mol) compared to Dic (-71.919 ± 19.717&#xa0;kJ/mol), dominated by van der Waals interactions. Carnosic acid demonstrates superior binding affinity, structural stability, and pharmacokinetic profile, positioning it as a promising candidate for Ag85C-targeted anti-<i>tuberculosis</i> drug development. These findings provide a robust foundation for further experimental validation and optimization toward novel therapies against drug-resistant TB.</p> Graphical Abstract <p></p>

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Carnosic Acid as a Potent Ag85C Inhibitor Identified Through Integrated Pharmacokinetic Evaluation and Molecular Modeling in Mycobacterium Tuberculosis Drug Discovery

  • 期刊论文

  • 发表日期：

    2025年10月29日

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  • Somayeh Farahmand,
  • Saber SamadiAfshar,
  • Reza HajiHosseini,
  • Toktam Babari

摘要

Abstract

Tuberculosis (TB) continues to pose a serious global health threat, particularly due to the emergence of drug-resistant strains that compromise current treatment regimens. The Antigen 85 (Ag85) complex, especially the Ag85C isoform, is a key virulence factor in Mycobacterium tuberculosis and a promising target for therapeutic intervention. We employed an integrated computational strategy to identify and characterize novel inhibitors targeting the Ag85C protein (PDB ID: 1DQY). Ligands were assessed for their drug-likeness and pharmacokinetics properties using SwissADME and PreADMET platforms. Molecular docking was performed using AutoDock Vina, followed by 200 ns molecular dynamics (MD) simulations with GROMACS and the AMBER99SB force field. MM/PBSA analysis quantified binding free energies and interaction mechanisms. Among screened compounds, Carnosic acid (Csa) and dihydrocurcumenone (Dic) were identified as lead inhibitors with binding energies of -7.95 and − 7.19 kcal/mol, respectively. Both exhibited high gastrointestinal absorption (> 92%) and favorable oral bioavailability. MD simulations confirmed the stability of ligand-protein complexes, with Root Mean Square Deviation (RMSD) values of 0.190 ± 0.014 nm for Csa and 0.154 ± 0.008 nm for Dic. MM/PBSA calculations revealed stronger binding affinity for Csa (-98.718 ± 17.087 kJ/mol) compared to Dic (-71.919 ± 19.717 kJ/mol), dominated by van der Waals interactions. Carnosic acid demonstrates superior binding affinity, structural stability, and pharmacokinetic profile, positioning it as a promising candidate for Ag85C-targeted anti-tuberculosis drug development. These findings provide a robust foundation for further experimental validation and optimization toward novel therapies against drug-resistant TB.

Graphical Abstract