Cyclobutanone analogues of β-lactams revisited: Insights into conformational requirements for inhibition of serine- and metallo-β- lactamases

Journal of the American Chemical Society

Volumn 132, Issue 8, 2010, Pages 2558-2560

  Johnson, Jarrad W ^a   Gretes, Michael ^b   Goodfellow, Valerie J ^a   Marrone, Laura ^a   Heynen, Miriam L ^a   Strynadka, Natalie C J ^b   Dmitrienko, Gary I ^a  

^a UNIVERSITY OF WATERLOO   (Canada)

^b UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVE SITE; BACTERIAL RESISTANCE; CARBAPENEMS; CHRYSEOBACTERIUM; CLASS A; CYCLOBUTANONES; ENZYME-INHIBITOR COMPLEX; FURTHER DEVELOPMENT; LACTAMASES; MEROPENEM; MOLECULAR MODELING STUDIES; STENOTROPHOMONAS MALTOPHILIA; X-RAY STRUCTURE;

AMIDES; AMINO ACIDS; CARBOXYLATION; MOLECULAR ORIENTATION; PHOSPHATASES;

KETONES;

BETA LACTAM; CARBAPENEM DERIVATIVE; CARBOXYLIC ACID; CYCLOBUTANONE DERIVATIVE; METALLO BETA LACTAMASE; SERINE; ALKANONE; ANTIINFECTIVE AGENT; BETA LACTAMASE;

ACHROMOBACTER; ACINETOBACTER; ARTICLE; BACTERIAL STRAIN; BIOCHEMISTRY; CITROBACTER; CONFORMATION; ENTEROBACTER CLOACAE; ESTERIFICATION; INHIBITION KINETICS; KLEBSIELLA; MOLECULAR MODEL; NONHUMAN; PROTON NUCLEAR MAGNETIC RESONANCE; PSEUDOMONAS; SERRATIA; SHIGELLA; X RAY CRYSTALLOGRAPHY; BACTERIUM; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; ENZYMOLOGY; METABOLISM;

ANTI-BACTERIAL AGENTS; BACTERIA; BETA-LACTAMASES; BETA-LACTAMS; BUTANONES; CRYSTALLOGRAPHY, X-RAY; MODELS, MOLECULAR;

EID: 77950411087     PISSN: 00027863     EISSN: 15205126     Source Type: Journal    
DOI: 10.1021/ja9086374     Document Type: Article

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42. Another potential contributing factor might involve disorder caused by a rapid conformational change of the inhibitor. Ab initio and DFT molecular modeling studies indicate that a model hemiketal of 4α can adopt two slightly different exo envelope conformations in which the chlorines show the greatest differences in position. The low energy difference (0.1 -0.3 kcal/mol) and the low energy barrier (0.4-0.8 kcal/mol) for interconversion support this hypothesis (Figures S3 and S4, Supporting Information).
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