Predicting the Activity of Boronate Inhibitors Against Metallo-β-lactamase Enzymes

Potency of boronate inhibitors against metallo-β-lactamases (MβLs) has been found to be dependent on the electrophilicity of the boron atom. It forms a covalent bond with the oxygen atom of the catalytic OH− ion in the active site of the enzyme. The ability of the boronate inhibitor to influence the protein conformation also affects the binding potency. Molecular dynamics (MD) simulations of cyclic and non-cyclic boronate complexes with NDM-1 MβL show their higher impact on the inhibitor efficiency compared with the electrophilicity of the boron atom. Therefore, we focus on the hardware impact on the computational speedup of the GPU-accelerated MD. Using this data, we propose a comprehensive protocol for in silico prediction of the activity of boronate molecules against MβL enzymes, which includes MD simulations, combined quantum mechanics / molecular mechanics (QM/MM) computations and molecular dynamics simulations with the QM/MM potentials (QM/MM MD) © The Authors 2022. This paper is published with open access at SuperFri.org