Interaction of antitubercular drug candidates with α1-acid glycoprotein produced in pulmonary granulomas.

The intracellular pathogen Mycobacterium tuberculosis can survive and replicate within host macrophages. Among various immunomodulatory substances, macrophages also produce α1-acid glycoprotein (AAG) which is secreted into the extracellular matrix of tuberculosis granulomas that represents a specific binding environment. Employing circular dichroism (CD) and UV/VIS absorption spectroscopic methods, we demonstrated and evaluated the AAG binding properties of novel antitubercular drug candidates developed against sensitive and multidrug-resistant strains of M. tuberculosis. As inferred from the CD spectroscopic data, these chemically diverse organic molecules are engulfed within the β-barrel of the protein either in a monomeric or dimeric form. Molecular docking simulations suggested the importance of H-bonds and ligand-aromatic residue π-π stacking interactions in stabilizing the drug molecules at the protein binding site. Based on the estimated Kd values (7-20 μM), AAG could be considered as the significant binding partner of the antitubercular agents studied herein. As such, it may affect the drug distribution and bioavailability not only in serum but also in macrophages and in the extracellular matrix of tuberculosis granulomas.