Effect of Substituents in Hydrolyzed Cephalosporins on Intramolecular O–H···N Bond (original) (raw)
Related papers
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.
Moscow University Chemistry Bulletin, 2019
⎯In this paper, the relationship of electronic steric factors in the active site of metallo-β-lactamase and reactivity of cephalosporin antibiotics is studied. The steric energy of the oxygen atom forming a temporary covalent bond in the structure of the transition state of the limiting stage characterizes the reactivity of the compounds. A linear relationship between this value and the macroscopic parameter of the stationary Michaelis-Menten kinetics (catalytic constant k cat) is proposed: the increase in the rate constant is associated with an increase in steric energy. Two-dimensional maps of the steric potential and steric energy density are analyzed.
Molecular Dynamics Simulations of the TEM-1 β-Lactamase Complexed with Cephalothin
Journal of Medicinal Chemistry, 2005
Herein, we present theoretical results aimed at elucidating the origin of the kinetic preference for penicillins over cephalosporins characteristic of the TEM/SHV subgroup of class A -lactamases. First, we study the conformational properties of cephalothin showing that the C2-down conformer of the dihydrothiazine ring is preferred over the C2-up one by ∼2 kcal/mol in solution (0.4-1.4 kcal/mol in the gas phase). Second, the TEM-1 -lactamase complexed with cephalothin is investigated by carrying out a molecular dynamics simulation. The ∆G binding energy is then estimated using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and quantum chemical PBSA (QM-PBSA) computational schemes. The preferential binding of benzylpenicillin over cephalothin is reproduced by the different energetic calculations, which predict relative ∆∆G binding energies ranging from 1.8 to 5.7 kcal/mol. The benzylpenicillin/ cephalothin ∆∆G binding energy is most likely due to the lower efficacy of cephalosporins than that of penicillins in order to simultaneously bind the "carboxylate pocket" and the "oxyanion hole" in the TEM-1 active site.
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.
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.
A b st ra ct— 7-(thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (cefovecin) is an antibiotic of the cephalosporin class. In silico binding free energy of six analogous structurally diverse cefovecin with Pseudomonas aeruginosa lipase were determined using Patchdock and Firedock softwares. The bonding interactions were also studied. The binding energy of cefovecin was-44.30 kcal/mol. The free binding energies of COOH, COCH3, CH3, NO2, CF3 and NH2 analogues were-44.30,-43.55,-39.49,-43.40,-30.25 and-44.18 Kcal/mol respectively. All the monosubstituted analogues showed lower negative values than the non substituted cefovecin. These lower negative values indicate that that the reactions are feasible. Their inhibition is lower compared to cefovecin against Pseudomonas aeruginosa lipase. The modes of bonding of six analogous structurally diverse cefovecin with Pseudomonas aeruginosa lipase were attributed to hydrogen bonding and steric interaction.
ChemInform, 1996
We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OHion on the 8-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OHion in approaching theb-lactam carbonyl group. Using the supermolecular approach and a H,O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).
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 °...