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Fragment-based discovery of 6-azaindazoles as inhibitors of bacterial DNA ligase.

ABSTRACT: Herein we describe the application of fragment-based drug design to bacterial DNA ligase. X-ray crystallography was used to guide structure-based optimization of a fragment-screening hit to give novel, nanomolar, AMP-competitive inhibitors. The lead compound 13 showed antibacterial activity across a range of pathogens. Data to demonstrate mode of action was provided using a strain of S. aureus, engineered to overexpress DNA ligase.

SUBMITTER: Howard S

PROVIDER: S-EPMC4027552 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Fragment-based discovery of 6-azaindazoles as inhibitors of bacterial DNA ligase.

Howard Steven S Amin Nader N Benowitz Andrew B AB Chiarparin Elisabetta E Cui Haifeng H Deng Xiaodong X Heightman Tom D TD Holmes David J DJ Hopkins Anna A Huang Jianzhong J Jin Qi Q Kreatsoulas Constantine C Martin Agnes C L AC Massey Frances F McCloskey Lynn L Mortenson Paul N PN Pathuri Puja P Tisi Dominic D Williams Pamela A PA

ACS medicinal chemistry letters 20131018 12

Herein we describe the application of fragment-based drug design to bacterial DNA ligase. X-ray crystallography was used to guide structure-based optimization of a fragment-screening hit to give novel, nanomolar, AMP-competitive inhibitors. The lead compound 13 showed antibacterial activity across a range of pathogens. Data to demonstrate mode of action was provided using a strain of S. aureus, engineered to overexpress DNA ligase. ...[more]

PMID: 24900632

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