Dual pharmacological targeting of Mycobacterium tuberculosis (Mtb) PKNA/PKNB: A novel approach for the selective treatment of TB illness | ||||
| Egyptian Journal of Chemistry | ||||
| Article 38, Volume 65, Issue 12, December 2022, Page 409-419 PDF (1.07 MB) | ||||
| Document Type: Original Article | ||||
| DOI: 10.21608/ejchem.2022.135419.5981 | ||||
 View on SCiNiTO | ||||
| Authors | ||||
Ali N. Hussein 1; Mohammed FAWZI2; Rasha Fadhel Obaid 3; Shaima Rabeea Banoon  4; Emad S Abood 5; Abdolmajid Ghasemian 6
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| 1Department of Pharmacy, Osol Aldeen University College, Baghdad, Iraq | ||||
| 2AL-Manara College For Medical Sciences, Department of Pharmacy, Maysan, Iraq | ||||
| 3Department of Biomedical Engineering, Al-Mustaqbal University College, Babylon, Iraq | ||||
| 4Department of Biology, College of Science, University of Misan, Maysan, Iraq | ||||
| 5Medical physics department, Hilla university college, Babylon, Iraq | ||||
| 6Noncommunicable diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran | ||||
| Abstract | ||||
| 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. | ||||
| Keywords | ||||
| IMB-YH-8; UCSF Chimera; Molecular Molegro Viewer (MMV); MODELER 9.19; GPU amber 14 software; LEAP module | ||||
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