The Effect of Chalcogen-Chalcogen Bond Formation in the New Delhi Metallo-β-Lactamase 1 Enzyme to Counteract Antibiotic Resistance.

New Delhi metallo-β-lactamase 1 (NDM-1) is an enzyme involved in the drug resistance of many bacteria against most of the widely adopted antibiotics, such as penicillins, cephalosporins, and carbapenems. Consequently, inhibiting NDM-1 swiftly has gained significant interest as a strategy to counteract this bacterial defense mechanism, thereby restoring the effectiveness of antibiotics. Among the inhibitors tested against the enzyme, ebselen (EbSe) showed particularly promising results. This molecule, renowned for its numerous benefits to the human body, targets the enzyme's active site at Cys208 with its selenium atom, facilitating the expulsion of the catalytic zinc ion from the active pocket. Since the inhibitory mechanism of EbSe remains poorly understood, gaining detailed information about it is highly desirable. In the present work, density functional theory calculations and μs-long molecular dynamics simulations are carried out to investigate the reaction mechanism of EbSe with NDM-1, unveiling the structural implications of the inhibition. A large model of the NDM-1 active site is built to investigate the different mechanistic proposals for the Se_EbSe-S_Cys208 bond formation. Deeper insights into Lys211 are also provided to consolidate its role during the inhibition process. Furthermore, the chemical reaction with the ebsulfur (EbS) molecule is also investigated to compare its behavior with that of the periodic relative selenium. Molecular dynamics simulations, besides evidencing the role of the L3 and L10 loops in the occurrence of the inhibition, corroborate the Zn ion release from the active site as a result of the complete disruption of its coordination sphere caused by the creation of the Se_EbSe-S_Cys208 covalent bond.