Electronic Steric Factors in the Active Site of Metallo-β-Lactamase and Reactivity of Cephalosporin Antibiotics (original) (raw)
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International Journal of Quantum Chemistry, 2020
The combined quantum mechanics/molecular mechanics (QM/MM) simulations of equilibrium geometry configurations followed by electron density analysis provide reliable quantitative structure-property relationship equations to estimate the reactivity of compounds in the active sites of enzymes. The main drawback is high computational cost of such calculations. Here, we report on a benchmark study aiming to optimize computational protocol for the accuracy of predictions. We considered an important example of cephalosporin hydrolysis in the active site of L1 metalloβ-lactamase and found that it is important to consider contributions to the one-electron part of the QM Hamiltonian from all MM system rather than using the cutoff of electrostatic interactions. Switching from the reference PBE0-D3/6-31G (d,p) QM protocol to the reduced PBE0-D3/6-31G scheme decreases the number of basis set functions by almost twice, increasing the error of the rate constant estimates up to 18 seconds −1 compared with the reference 10 seconds −1. Therefore, the QM(PBE0-D3/6-31G)/MM(AMBER) level of theory can be recommended for estimates of cephalosporin reactivity in the search of new antibiotics.
Physical Chemistry Research, 2017
Metallo-β-lactamases (MβL) catalyzing the hydrolytic cleavage of the four-membered β-lactam ring in broad spectrum of antibiotics and therefore inactivating the drug; However, the mechanism of these enzymes is still not well understood. Electronic structure and electronic energy of metallo-β-lactamase active center, two inhibitors of this enzyme including penicillin and cephalexin, and different complexes between these inhibitors and active center of metallo-β-lactamase have been investigated. For both substrates (S), the nucleophilic attack of the substrate amide group to model’s active site dinuclear zinc (E) formed an ES reactive complex that by passing through the first transition state (TS1), first intermediate (INT1), the second intermediate (INT2) and second transition state (TS2) converted to the product. Also, all the thermodynamic functions, ∆Ho, ∆So and ∆Go, to form two transition states, TS1 and TS2, and for the total reaction for two MβL inhibitors are evaluated at 25 °...
Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-β-lactamase
Archives of Biochemistry and Biophysics, 2015
In this paper, hybrid QM/MM molecular dynamics (MD) simulations have been performed to explore the mechanisms of hydrolysis of two antibiotics, Imipenen (IMI), an antibiotic belonging to the subgroup of carbapenems, and the Cefotaxime (CEF), a third-generation cephalosporin antibiotic, in the active site of a mono-nuclear βlactamase, CphA from Aeromonas hydrophila. According to our results, significant different transition state structures are obtained for the hydrolysis of both antibiotics: while the TS of the CEF is a ionic species with negative charge on nitrogen, the IMI TS presents a tetrahedral-like character with negative charge on oxygen atom of the carbonyl group of the lactam ring. Thus, dramatic conformational changes can take place in the cavity of CphA to accommodate different substrates, which would be the origin of its substrate promiscuity. This feature of the β-lactamase would be in turn, associated to the different mechanisms that the protein employs to hydrolyze the different antibiotics; i.e. the catalytic promiscuity. Since CphA shows only activity against carbapenem antibiotic, this study will be used to shed some light into the origin of the selectivity of the different MbL and, as a consequence, into the discovery of specific and potent MβL inhibitors against a broad spectrum of bacterial pathogens.
Effect of Substituents in Hydrolyzed Cephalosporins on Intramolecular O–H···N Bond
Russian Journal of Physical Chemistry A, 2020
Model molecular systems structurally similar to the transition state of the limiting step of the hydrolysis of cephalosporin antibiotics by the L1 metallo-β-lactamase are studied. The series of fluorinated compounds show that the nature of substituents in thiazine and β-lactam rings have a great impact on the strength of the intramolecular O-H•••N hydrogen bond that determines the catalytic parameters in real biological systems. The strengthening or weakening of the O-H•••N bond is registered via a quantum topological analysis of the electron density, supplemented with various bonding descriptors' study. The obtained data are confirmed by the analysis of the vibrational frequency shift relatively to the nonfluorinated compound for the O-H stretching mode of the carboxylic group involved in the O-H•••N bond formation. The absence of the monotonic dependence of the hydrogen bond strength on the donor-acceptor effects of substituents shows that considered bonding descriptors do not provide a complete understanding of the bonding mechanisms in the active center of L1 metallo-β-lactamase.
A study of the nucleophilic attack of the beta-lactamic bond of antibiotics in water solution
Journal of Molecular Structure: THEOCHEM, 2001
The nucleophilic attack of a series of 19 b-lactamic antibiotics (13 penicillins and six cephalosporins), as well as that of the clavulanic acid (CLA), by a hydroxylic anion, is considered in water solution and in gas phase. It is found that the tetrahedral intermediate formation does not occur spontaneously anymore in water solution, but the reaction has to overpass an energy barrier due to the desolvation of the reactants. The desolvation energy barriers, as well as the tetrahedral complex formation energy in water solution are calculated into the PM3 semi-empirical approach and the supermolecule model. In the same way, the energy barriers for the b-lactamic bond breaking and the ®nal product formation energies are determined. The results are compared with those obtained previously for the same molecules in the gas phase.
Coupling Reactions of Cephalosporin Sulfones: A Stable 3-Stannylated Cephem
Organic Letters, 2001
The first stable 3-metalated cephalosporin is reported and shown to be an excellent synthetic precursor to a number of prospective-lactamase inhibitors. One highly effective method for countering antibioticresistant microorganisms is the co-administration of an antibiotic and a-lactamase inhibitor. 1-Lactamase represents a collection of bacterial enzymes (classes A, B, C, and D) that effectively hydrolyze-lactam antibiotics. Historically, the most clinically important of these were the plasmidmediated class A enzymes. 2 However, in recent years, bacterial resistance mediated by class B, C, and D enzymes has become increasingly significant. 3 Current commercial inhibitors target only class A-lactamases. 1 Our group has recently described classes of compounds that simultaneously inhibit both class A and class C-lactamases. 4 We have designed new inhibitors both of the penicillin and of the cephalosporin skeleton. Unlike the corresponding penicillin and cephalosporin antibiotics, however, these new compounds have the sulfur in the sulfone oxidation state and have an alkylidene side chain in place of the more common acylamido side chain at C6 (penam) or C7 (cephem). Some examples are shown in Figure 1. Figure 1. Representative-lactamase inhibitors containing an R-alkylidene-lactam substructure.
Computational analysis of the interactions of a novel cephalosporin derivative with β-lactamases
BMC Structural Biology
Background: One of the main concerns of the modern medicine is the frightening spread of antimicrobial resistance caused mainly by the misuse of antibiotics. The researchers worldwide are actively involved in the search for new classes of antibiotics, and for the modification of known molecules in order to face this threatening problem. We have applied a computational approach to predict the interactions between a new cephalosporin derivative containing an additional β-lactam ring with different substituents, and several serine β-lactamases representative of the different classes of this family of enzymes. Results: The results of the simulations, performed by using a covalent docking approach, has shown that this compound, although able to bind the selected β-lactamases, has a different predicted binding score for the two βlactam rings, suggesting that one of them could be more resistant to the attack of these enzymes and stay available to perform its bactericidal activity. Conclusions: The detailed analysis of the complexes obtained by these simulations suggests possible hints to modulate the affinity of this compound towards these enzymes, in order to develop new derivatives with improved features to escape to degradation.