Evaluating the binding potency of the carbapenem (T208) ligand and modelled non-halogen (NH2 and SH) and halogen (Br, Cl, F) derivatives in Mycobacterium tuberculosis L. D-transpeptidase

Improvements in medication are required because number of tuberculosis (TB)-related deaths increase during COVID-19 pandemic. Reducing efficiency of current therapeutic agents require creation of novel medications that aim specific targets and avoid existing resistance mechanisms. In this study, we had focused on tuberculosis, most deadly infection, which threatens humanity in the 20th century after COVID-19, and world's leading cause of infection-related mortality. Our main goal in this study was to understand the stability and potency of carbapenem (T208) ligands and their modelled derivatives (Br, Cl, F, NH₂, and SH) through hydrogen and halogen bond interactions that holds ligand-amino acid contact in the hinge region. This information will provide a clear picture of structural and binding characteristics of protein-ligand interactions. Further, this will aid chemists in creating new carbapenem ligands, which are expected to reduce the action of β-lactamase enzyme and serve as anti-TB drugs. The binding strength of carbapenem ligands with interacting hinge region amino acid side chains: tryptophan (Trp-340), histidine (His-336), histidine (His-352), cystine (Cys 354), and tyrosine (Tyr 318) were analyzed through interaction energies calculated at HF, M062X, M06HF, B3PW91, and MP2 level of theories for various basis sets (6-311G∗∗, SDD). Overall, derivatives of halogen atoms (Br, Cl, and F) and NH₂ enhanced the binding strength of T208 in β-lactamase enzymes. This opened up a new and unique pathway for derivatives preference on ligand that perfectly encloses amino acid in the hinge region.