A semiempirical molecular orbital study of the methanolysis of complex azetidinones. A combined MM and QM analysis of the interaction of Δ<sup>2</sup>- and Δ<sup>3</sup>-cephems with the penicillin receptor

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The docking of penicillins to a computer model of the active site of the penicillin-binding protein of Streptornyces R61 produces structures that exhibit a four-centred interaction between the 0 -H of a serine residue and the (0)C-N of the p-lactam ring. If such a structure is a stationary point on the reaction coordinate for the acylation of the serine OH by the p-lactam carbonyl group, the acylation mechanism would appear to consist of 0-C and H-N bond formation, concerted with the cleavage of the C-N bond. The existence of this "N-protonation" mechanism, and the energetics of this mechanism in comparison to the usual "0-protonation" pathway in which proton transfer to oxygen and addition to the carbonyl group precede C-N bond fission, have been examined by ab initio M O calculations on the neutral hydrolysis and methanolysis of N-methylazetidinone, penam, and penam-3a-carboxylate. The geometries of reactants and transition structures have been optimized fully at the 3-21G or 3-21G* levels, the existence of transition structures has been confirmed by vibrational analysis, thermochemical data have been computed, and the one-point energies of all structures have been determined at the MP216-31G* level. The N-protonation mechanism is found to exist with all substrates, and to be preferred over the 0-protonation mechanism by over 5 kcallmol. The activation energies are 5 kcallmol lower in the bicyclic penam than in the monocyclic N-methylazetidinone, and attack from the convex face is preferred over attack from the concave face. The introduction of a 3a-carboxylate group, as in penicillin itself, results in an additional 5 kcallmol decrease in activation energy. The origins of these trends are discussed. Since the active sites of some penicillin-recognizing enzymes contain at least one water molecule, catalysis of the foregoing reactions by one water molecule has also been examined. The catalysis amounts to over 10 kcaVmol in both the N-and 0-protonation mechanisms, and the preference for the N-protonation mechanism is maintained. It is concluded that penicillin complexes to its receptor in such a manner as to allow acylation of the active site serine residue to proceed via the energetically most favourable mechanism. SAUL WOLFE, CHAN-KYUNG KIM et KIYULL YANG. Can. J. Chem. 72, 1033Chem. 72, (1994. L'ammage de pCnicillines au modble sur ordinateur du site actif de la protCine de liaison de la pCnicilline du Streptomyces R61 foumit des structures qui prCsentent une interaction 21 quatre centres entre le 0 -H de la sCrine et le (0)C-N du noyau p-lactame. Si une telle structure est un point stationnaire sur les coordonnCes rtactionnelles de l'acylation du OH de la sCrine par le groupe carbonyle du p-lactame, il semblerait que le mtcanisme d'acylation cornporterait la formation de liaisons 0-C et H-N concertCe avec un clivage de la liaison C-N. L'existence de ce mCcanisme de ccN-protonation, et les tnergies impliquCes dans ce mCcanisme, par comparaison avec la voie usuelle de ccO-protonation,, dans laquelle le trans...

Section: Resultsmentioning

confidence: 99%

Ab initio molecular orbital calculations on the neutral hydrolysis and methanolysis of azetidinones, including catalysis by water. Relationship to the mechanism of action of β-lactam antibiotics

Wolfe¹,

Kim²,

Yang³

1994

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“…This treLd is typical. As discussed elsewhere (14) , energies of the N-and 0-protonated reaction pathways. In addition, MIND013 calculations of the activation energies for the / methanolyses of azetidinones provide structure-reactivity trends that parallel the trends in the structure-activity relations I of penicillins and cephalosporins (14).…”

Section: Targeting a Pbpmentioning

confidence: 95%

“…As discussed elsewhere (14) , energies of the N-and 0-protonated reaction pathways. In addition, MIND013 calculations of the activation energies for the / methanolyses of azetidinones provide structure-reactivity trends that parallel the trends in the structure-activity relations I of penicillins and cephalosporins (14). Therefore, the MIND01 I 3 semiempirical procedure was used for a preliminary survey of more general relationships between structure and four-centred reactivity towards methanol.…”

Section: Targeting a Pbpmentioning

confidence: 95%

“…Previously unknown MM2 parameters were found, where necessary, using established procedures (14,16). The parameters thus determined for the compounds to be discussed below are available as Supplementary ate rial.^ Each candidate was docked to 3 via the two hydrogen bonds already noted, and the relationship between the C=N of the candidate and the 0 -H of ser3 in the resulting complex was examined.…”

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confidence: 99%

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Interactive design and synthesis of a novel antibacterial agent

Wolfe¹,

Jin²,

Yang³

et al. 1994

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. Can. J. Chem. 72, 105 1 (1994). P-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e.,fit) and catalytic (i.e. reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP from Streptomyces R61, the use of molecular mechanics calculations to treat "fit," and ab initio molecular orbital calculations to treat "reactivity," leads to the idea that the carboxyl group (GI) and the amide N-H (G2) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme-substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the p-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the p-lactam nitrogen. Molecular orbital calculations of structure-reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the p-lactam N-C(=O), comparable to a p-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (-AE > 10 kcaUmo1). Accordingly, structures containing a G1 and a G2 separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-l,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropy1)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, from D-and L-serine. The compound derived from L-serine is not active. The compound derived from D-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be canied out if modification of the lead structure leads to compounds with improved chemical stability. Toutefois, des essais prkliminaires ont suggCrC que le C=N de ce composC serait en Cquilibre avec les Cnamines endocycliques et exocycliques tautombres. Cette caractkristique nCcessite que la position C2 soit substituCe et que le groupe hydroxyle ne soit pas attach6 au carbone adjacent du C=N. On rencontre ces conditions dans une 2,2-dimCthy1-3-(2...

“…We believe that, had only the crystal structure been available to us, we would have expected the amide N-H to be buried in the interior of the molecule, and would not have examined its participation in the complexation. Figure 13 shows 7,8, and 16, the 4-epi isomer of 8, docked to the model of the penicillin receptor (55). In each case we observe the same kind of relationship between the serine hydroxyl group and the convex face of the antibiotic.…”

Section: Theoretical Studiesmentioning

confidence: 82%

1992 Lemieux Award Lecture Studies related to the penicillin receptor

Wolfe¹

1994

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The relative antibacterial activities of penicillins and cephalosporins are discussed in terms of their differing abilities to complex to and react with penicillin-binding proteins. The insights gained from such an analysis are being used to attempt the design of new kinds of structures targeted to the penicillin receptor. Details of such design, and examples of several new classes of compounds suggested by this work, are described. Some of these compounds exhibit interesting antibacterial activity.