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

Steven Howard,Nader Amin,Andrew B Benowitz,Elisabetta Chiarparin,Haifeng Cui,Xiaodong Deng,Tom D Heightman,David J Holmes,Anna Hopkins,Jianzhong Huang,Qi Jin,Constantine Kreatsoulas,Agnes C L Martin,Frances Massey,Lynn McCloskey,Paul N Mortenson,Puja Pathuri,Dominic Tisi,Pamela A Williams

ACS medicinal chemistry letters（2013）

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摘要

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.

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关键词

bacterial dna ligase,s. aureus,fragment-based drug design,structure-based optimization

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