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The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications.


ABSTRACT: Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10?µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity. These hit compounds were then rescreened against the target in 8-point dose-response curves and 11 compounds were found to inhibit enzymatic activity with IC50 values of less than 10?µM. Finally, compounds (1-5) were docked against RpMetAP with AutoDock to determine potential binding mechanisms and the results were compared with crystal structures deposited within the PDB.

SUBMITTER: Helgren TR 

PROVIDER: S-EPMC5908248 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications.

Helgren Travis R TR   Seven Elif S ES   Chen Congling C   Edwards Thomas E TE   Staker Bart L BL   Abendroth Jan J   Myler Peter J PJ   Horn James R JR   Hagen Timothy J TJ  

Bioorganic & medicinal chemistry letters 20180315 8


Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a  ...[more]

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