Evaluating the covalent binding of carbapenems on BlaC using noncovalent interactions.

Carbapenems, as irreversible covalent binders and slow substrates to the class A β-lactamase (BlaC) of Mycobacterium tuberculosis, can inhibit BlaC to hydrolyze the β-lactam drugs which are used to control tuberculosis. Their binding on BlaC involves covalent bonding and noncovalent interaction. We introduce a hypothesis that the noncovalent interactions dominate the difference of binding free energies for covalent ligands based on the assumption that their covalent bonding energies are the same. MM/GBSA binding free energies calculated from the noncovalent interactions provided a threshold with respect to the experimental kinetic data, to select slow carbapenem substrates which were either constructed using the structural units of experimentally identified carbapenems or obtained from the similarity search over the ZINC15 database. Combining molecular docking with consensus scoring and molecular dynamics simulation with MM/GBSA binding free energy calculations, a computational protocol was developed from which several new tight-binding carbapenems were theoretically identified.