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

Elena O. Levina; Maria G. Khrenova; Vladimir G. Tsirelson

doi:10.14529/jsfi220202

Authors

Elena O. Levina A.N. Bach Institute of Biochemistry, Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, Moscow, Russia https://orcid.org/0000-0003-4532-9187
Maria G. Khrenova A.N. Bach Institute of Biochemistry, Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, Moscow, Russia https://orcid.org/0000-0001-7117-3089
Vladimir G. Tsirelson Mendeleev University of Chemical Technology, Moscow, Russia https://orcid.org/0000-0002-8610-9116

DOI:

https://doi.org/10.14529/jsfi220202

Keywords:

metallo-β-lactamase, boronate inhibitors, MD, QM/MM MD, quantum theory of atoms in molecules (QTAIM), GPU-accelerated algorithms

Abstract

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).

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