Dual pharmacological targeting of Mycobacterium tuberculosis (Mtb) PKNA/PKNB: A novel approach for the selective treatment of TB illness

As drug-resistant tuberculosis (TB) infections grow more widespread, antibiotics that inhibit Mycobacterium tuberculosis through a novel technique might be an important component of changing TB therapy. In M. tuberculosis, protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases. These enzymes present an intriguing option for antimycobacterial drug discovery, given the large knowledge base in kinase inhibition. A recent experimental study shows that IMB-YH-8 acts as a dual PknA/ PknB inhibitor. However, its methods of selectivity and inhibition at the molecular level have yet to be fully elucidated. Molecular dynamics simulations have been used to probe the inhibitory mechanism and the selectivity impact, yielding important insights into the reported inhibitory effect. MD simulation reveled that IMB-YH-8 selectively targeted the hinge-binding pocket residues, with the acetophenone group interacting into the small hydrophobic pocket provided by Met143 and Val 23 in PknA, and by the analogue’s residues Met 92 and Val 25 in PknB. Identification of the hinge-binding site residues could open the way toward the structure-based design of a novel structure-based design of highly PknA/PknB selective inhibition in the treatment of Mycobacterium tuberculosis.