Identification of potential inhibitors of Mycobacterium tuberculosis PknA using integrative molecular modeling approaches

Tuberculosis (TB) is one of the leading causes of mortality worldwide. Although it is considered a curable disease, the emergence of strains resistant to conventional treatments has rendered it a significant public health problem. Therefore, it is necessary to identify new therapeutic targets to combat this disease. The serine/threonine protein kinase A (PknA) has gained relevance due to its essential role in cell wall synthesis and the growth of Mycobacterium tuberculosis (Mtb). In the present study, an integrative molecular modeling approach was developed for the screening of libraries containing 1 581 625 compounds to identify potential PknA inhibitors. Pharmacophore-based virtual screening, followed by molecular docking, steered molecular dynamics, and binding free energy calculations have identified compound CHEMBL552033 as a promising hit compound. In addition, in silico ADME profiling, pharmacophore-based toxicity assessment, and kinase selectivity screening were performed to evaluate overall suitability as a promising hit. Molecular dynamics simulations of the PknA–CHEMBL552033 complex demonstrated the stability of the interaction, and the binding free energy values obtained by MM-GBSA (−49.54 ± 7.08 kcal/mol) and LIE-D method (−7.01 ± 1.26 kcal/mol) emphasize the potential of CHEMBL552033 as a potential inhibitor for the development of novel anti-TB therapies.