Insight into Lactam Antibiotics and their Receptors from Computational Chemistry

Boyd, Donald B.; Snoddy, John D.

doi:10.1007/978-3-662-02740-0_1

Cited by 6 publications

(3 citation statements)

References 49 publications

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“…Recently, a number of theoretical studies have appeared that attempt to address some of the more specific details of the microscopic mechanism for the hydrolysis of amide linkages in general. − Several studies have combined classical mechanics with kinetics studies to investigate various β-lactamase mutations. Juteau et al.…”

Section: Introductionmentioning

confidence: 99%

“…Molecular mechanics applications have also been used independently to refine structural models previously determined through X-ray crystallography. Boyd and Snoddy utilized gas-phase as well as solvated models to examine the structure of two complete penicillin-recognizing proteins. A more complete gas-phase structure for a class A β-lactamase was similarly determined by Bunster et al.…”

Section: Introductionmentioning

confidence: 99%

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Acylation of β-Lactams by Class A β-Lactamase: Anab InitioTheoretical Study on the Effects of the Oxy-Anion Hole

et al. 1997

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The initial acylation step in the -lactamase catalyzed hydrolysis of -lactams is studied using an ab initio quantum mechanical approach. The computational model incorporates a simple -lactam substrate and key residues found in the active site in order to assess the plausibility of a specific mechanism originally proposed by Strynadka et al. 1 and to estimate the stabilizing effects of the oxy-anion hole components founds in these enzymes. The computational model was constructed using information obtained from a high resolution X-ray crystal structure of unbound native -lactamase, isolated from Staphylococcus aureus PC1. Within this model, the overall acylation reaction was found to occur with modest activation energy <26 kcal mol -1 (<109 kJ mol -1 ) through a microscopic pathway characterized by discrete proton transfer steps between the substrate and the active site residues Ser-70, Lys-73, and Ser-130. These energetic results are considerably lower than the activation energies found for the uncatalyzed hydrolysis of simple amides in the gas phase. Interestingly, the energetic stabilization of the components, which make up the oxy-anion hole, were found to be modest with only one stationary point on the potential energy surface being significantly reduced by ∼8 kcal mol -1 (∼33 kJ mol -1 ).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acylation of β-Lactams by Class A β-Lactamase: Anab InitioTheoretical Study on the Effects of the Oxy-Anion Hole

et al. 1997

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“…The same situation is also observed for cephalosporins, where a wide latitude in 3-position side chains can be accommodated.2229 How the side chains are oriented and the mechanism of the acylation can be studied by further computations using, for instance, the geometries of the active site of two /3-lactam-recognizing enzymes, a transpeptidase and a /3-lactamase, that have been refined by recent molecular dynamics simulations. 30 The results of medicinal chemistry on the bicyclic pyrazolidinones were dramatic. In a relatively short time, the spectrum and potency were improved from being modest for the earliest bicyclic pyrazolidinone (MICs in the range 8-128 gg/mL)4 to that of third-generation cephalosporins for the methyl sulfone derivative.…”

Section: Discussionmentioning

confidence: 99%

Application of the hypersurface iterative projection method to bicyclic pyrazolidinone antibacterial agents

Boyd

1993

J. Med. Chem.

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Bicyclic pyrazolidinones are a class of synthetic antibacterial agents in which the beta-lactam ring is replaced by a five-membered ring. These compounds possess electronic and shape properties required for inhibiting penicillin-binding proteins essential for bacterial cell growth. A novel approach called the hypersurface iterative projection (HIP) method, which is based on three-dimensional computer graphics, allows available structure-activity information to be extrapolated to new synthetic targets. By updating the data set as the SAR evolves, the computer graphics reveal regions of parameter space to explore for optimum activity and regions yet unexplored. A large substituent parameter database is used to propose appropriate substituents. For the bicyclic pyrazolidinones, lipophilicity and particularly electron-withdrawing properties of the 3-substituent are shown to correlate strongly with minimum inhibitory concentrations (MIC). Antibacterial potency is intimately related to the activating effect of 3-substituents on chemical reactivity. The HIP method succeeded in proposing the most potent member of the series prior to synthesis and also showed when all of parameter space was reasonably well explored to the extent the chemistry allowed.

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Molecular Modeling

Boyd¹

2000

Ullmann's Encyclopedia of Industrial Chemistry

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Insight into Lactam Antibiotics and their Receptors from Computational Chemistry

Cited by 6 publications

References 49 publications

Acylation of β-Lactams by Class A β-Lactamase: Anab InitioTheoretical Study on the Effects of the Oxy-Anion Hole

Acylation of β-Lactams by Class A β-Lactamase: Anab InitioTheoretical Study on the Effects of the Oxy-Anion Hole

Application of the hypersurface iterative projection method to bicyclic pyrazolidinone antibacterial agents

Molecular Modeling

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