Abstract
Boronic acids are prospective compounds in inhibition of metallo-β-lactamases as they form covalent adducts with the catalytic hydroxide anion in the enzymatic active site upon binding. We compare this chemical reaction in the active site of the New Delhi metallo-β-lactamase (NDM-1) with the hydrolysis of the antibacterial drug imipenem. The nucleophilic attack occurs with the energy barrier of 14 kcal/mol for imipenem and simultaneously upon binding a boronic acid inhibitor. A boron atom of an inhibitor exhibits stronger electrophilic properties than the carbonyl carbon atom of imipenem in a solution that is quantified by atomic Fukui indices. Upon forming the prereaction complex between NDM-1 and inhibitor, the lone electron pair of the nucleophile interacts with the vacant p-orbital of boron that facilitates the chemical reaction. We analyze a set of boronic acid compounds with the benzo[b]thiophene core complexed with the NDM-1 and propose quantitative structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated descriptors of electron density. These relations are applied to classify other boronic acids with the same core found in the database of chemical compounds, PubChem, and proposed ourselves. We demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid inhibitors are 30–70 μM.
Highlights
Bacterial resistance is known from the very beginning of the penicillin era [1,2,3,4]
We study the mechanism of this chemical reaction and compare it with the same nucleophilic addition step during the hydrolysis reaction of the imipenem substrate
Application of molecular dynamics simulations with the QM/MM potentials complemented with on-the-fly calculations of electron density-based descriptors allowed us to study and compare nucleophilic attacks of the catalytic species in the NDM-1 active site
Summary
Bacterial resistance is known from the very beginning of the penicillin era [1,2,3,4]. We performed an analysis of electron density-based and geometry descriptors at the stationary points on potential energy surfaces and along QM/MM trajectories. In the latter case, we selected a set of 100 MD frames distributed along each considered MD trajectory. We calculated electron density-based descriptors at bond-critical points (BCPs) corresponding to the coordination bonds between the zinc cations and hydroxyboronate anion-containing inhibitors (cpd1–cpd15) at minima on potential energy surfaces. These are electron density, ρ(r), and Laplacian of electron density, ∇2ρ(r). These are evaluated as differences between Hirshfeld charges [65] calculated for the model system with N electrons (as it is set in the calculations) and N + 1 electrons [66,67,68]
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