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Boronic Acids As Prospective Inhibitors of Metallo–Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Reveal

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Boronic Acids As Prospective Inhibitors of Metallo–Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Reveal molecules Article Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling Alexandra V. Krivitskaya 1 and Maria G. Khrenova 1,2,* 1 Bach Institute of Biochemistry, Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, 119071 Moscow, Russia; [email protected] 2 Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia * Correspondence: [email protected] 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 Citation: Krivitskaya, A.V.; structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated Khrenova, M.G. Boronic Acids as descriptors of electron density. These relations are applied to classify other boronic acids with the Prospective Inhibitors of same core found in the database of chemical compounds, PubChem, and proposed ourselves. We Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid Active Site Revealed by Molecular inhibitors are 30–70 µM. Modeling. Molecules 2021, 26, 2026. https://doi.org/10.3390/ Keywords: NDM-1; metallo-β-lactamase; bacterial resistance; benzo[b] thiophene; boronic acid molecules26072026 inhibitor; QM/MM; QTAIM; QM/MM molecular dynamics Academic Editor: Marko Golicnikˆ Received: 17 March 2021 1. Introduction Accepted: 1 April 2021 Bacterial resistance is known from the very beginning of the penicillin era [1–4]. One Published: 2 April 2021 of the mechanisms is attributed to the hydrolytic activity of the bacterial enzymes towards β-lactams. These enzymes are called β-lactamases (BLs), and they hydrolyze the C–N Publisher’s Note: MDPI stays neutral bond of the β-lactam ring of antibiotics forming the inactivated compounds, β-amino with regard to jurisdictional claims in acids [5,6]. The antibiotic hydrolysis is initiated by various nucleophiles depending on published maps and institutional affil- β β iations. the particular type of -lactamases [6,7]. The B class BLs are metallo- -lactamases (MBLs) that comprise one or two zinc cations in the active site [7]. These are divided into three subclasses, B1, B2, and B3 [8,9]. The most clinically relevant representative in the B1 subclass is the NDM-1 (New Delhi metallo-β-lactamase-1) [10]. It demonstrates substrate promiscuity [11], including hydrolysis of carbapenems [12]. In addition, it causes particular Copyright: © 2021 by the authors. alertness due to its high spread between different bacterial species by lateral gene transfer Licensee MDPI, Basel, Switzerland. favored by globalization and travel [13]. This article is an open access article The active site of NDM-1 contains two zinc cations, Zn12+ and Zn22+, bridged by a distributed under the terms and catalytic hydroxide ion, OH−. The first zinc cation (Zn12+) is coordinated by His120, His122 conditions of the Creative Commons 2+ Attribution (CC BY) license (https:// and His189, while the second zinc cation (Zn2 ) is coordinated by Asp124, Cys208 and 2+ creativecommons.org/licenses/by/ His250 (Figure1A). In the binding site, Zn1 orients and polarizes the carbonyl group of 4.0/). the substrate, facilitating the chemical reaction. The above-mentioned hydroxide anion is a Molecules 2021, 26, 2026. https://doi.org/10.3390/molecules26072026 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 13 Molecules 2021, 26, 2026 2 of 13 the substrate, facilitating the chemical reaction. The above-mentioned hydroxide anion is a nucleophilenucleophile thatthat initiatesinitiates a a chemical chemical reaction reaction by by the the attack attack on on the theβ -lactamβ-lactam ring, ring, eventually eventu- allyleading leading to substrateto substrate hydrolysis hydrolysis (Figure (Figure1B) [18B].) Since[8]. Since the discoverythe discovery of NDM-1 of NDM [14-],1 many[14], manyinhibitors inhibitors of various of various nature n haveature been have proposed. been proposed However,. However none of, none them of has them been has clinically been clinicallyapproved approved [8,15]. These [8,15]. are Th naturalese are plant-based natural plant compounds-based compounds [16,17], synthetic [16,17], synthetic low molecular low molecularweight inhibitors weight inhibitors [10,18–22], [10,18β-lactams–22], [β23-lactams–26], amino [23– acid26], amino derivatives acid andderivatives peptides and [27 ]. peptidesBoron-based [27]. Boron inhibitors-based attract inhibitors special attract attention special [28– 30attention]. Recent [28 advances–30]. Recent in developing advances thein developingtherapeutically the therapeutically relevant boron-containing relevant boron compounds-containing [31 ,compounds32] even resulted [31,32] in even the FDA- re- sultedapproved in the anticancer FDA-approved drug bortezomib anticancer [33 drug]. From bortezomib the chemical [33]. viewpoint, From the thesechemical compounds view- point,are Lewis these acidscompounds and can are react Lewis reversibly acids and with can biologically react reversibly relevant with nucleophilesbiologically relevant via their nucleophilesvacant p-orbitals via their [34 vacant–37]. They p-orbitals form [34 covalent–37]. They tetrahedral form covalent products, tetrahedral hydroxyboronate products, hydroxyboronateanions, upon reaction anions, with upon the reaction nucleophilic with hydroxidethe nucleophilic anion hydroxide in the active anion site in of the NDM-1 ac- tive(Figure site o1C)f NDM [18,35-1]. (Figure 1C) [18,35]. (A) (B) His189 2 2 R R His120 1 1 R R Cys208 S S N – N O O OwH - Zn22+ HO O O w O – O – Zn12+ (C) - His250 His122 OH – HO1 B HO1 B O2H O2H Asp124 - HO w HO w Figure 1. A β B Figure 1. (A() The) The active active site site of ofNDM NDM-1-1 metallo metallo--β-lactamase-lactamase (left). (left). Nucleophilic Nucleophilic attack attack step step during during (B) (the) thehydrolysis hydrolysis of C imipenemof imipenem and and(C) conversion ( ) conversion of boronic of boronic acid acidto hydroxyboronate to hydroxyboronate anion. anion. The C TheB atoms CB atomsof the ofside the chains side chainsof amino of aminoacids onacids the QM/MM on the QM/MM border are border shown are in shown the ball in’ thes representation. ball’s representation. Color code: Color zinc code:—cyan, zinc—cyan, oxygen– oxygen–red,red, sulfur— sulfur—yellow,yellow, nitro- gennitrogen—blue,—blue, hydrogen hydrogen—white;—white; carbon carbon is green is greenin complexes in complexes with imipenem with imipenem and lavender and lavender in complexes in complexes with cpd5. with cpd5. InIn this this work, work, we we focus focus on ontwo two features features of boron of boron-containing-containing inhibitors. inhibitors. First, we First, com- we − parecompare interactions interactions between between the nucleophilic the nucleophilic OH- of the OH NDMof the-1 active NDM-1 site activeand its site substrate and its imipenemsubstrate with imipenem one of withthe boronic one of theacid boronic inhibitor acids (cpd5 inhibitors, according (cpd5, to according Ref. [26]). toTo Ref. do this, [26]). weTo calculate do this, wethe Gibbs calculate energy the Gibbsprofiles energy of the profilesnucleophilic of the attack nucleophilic step using attack molecular step using dy- namicmoleculars (MD) dynamics simulations (MD) with simulations the combined with the quantum combined mechanics/molecular quantum mechanics/molecular mechanics QM(PBE0mechanics-D3/6 QM(PBE0-D3/6-31G**)/MM-31G**)/MM potentials. Additionally, potentials. Additionally, we compare we the compare dynami thec behavior dynamic ofbehavior the corresponding of the corresponding reactant complexes reactant complexeswith the same with compounds the same compounds in water solution in water, measuringsolution, measuringatomic Fukui atomic electrophilicity Fukui electrophilicity indices of the indices carbonyl of the carbon carbonyl (in an carbon imipenem) (in an andimipenem) boron (in and a boronic boron (inacid a boronicinhibitor) acid atoms. inhibitor) Next, atoms.we consider Next, five we considerboronic acid five inhibi- boronic acid inhibitors with the benzo[b]thiophene core with known IC50 values (concentration tors with the benzo[b]thiophene core with known IC50 values (concentration of inhibitor of inhibitor that results in 50% inhibition of the enzyme activity) [26] corresponding to that results in 50% inhibition of the enzyme activity) [26] corresponding to the NDM-1 the NDM-1 inhibition. We study covalent adducts, hydroxyboronate anions in the active inhibition.
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