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Identification of an auxiliary druggable pocket in DNA gyrase ATPase domain using fragment probes


Discovery of new drug binding sites on well-established targets is of great interest as it facilitates designing new mechanistic inhibitors to overcome the acquired drug resistance. The small chemical fragments can easily enter and bind to the cavities on protein surface. Thus they can be used to probe new druggable pockets in proteins. DNA gyrase plays indispensable roles in DNA replication, and its both GyrA and GyrB subunits are clinically validated antibacterial targets. The new mechanistic GyrB inhibitors are urgently desired since the withdrawal of novobiocin from the market by FDA due to its reduced efficiency and other reasons. Here, a fragment library was screened against E. coli GyrB ATPase domain by combining affinity- and bioactivity-based approaches. The following X-ray crystallographic efforts determined cocrystal structures of GyrB with ten fragment hits, and three different binding modes were disclosed. Fortunately, a hydrophobic pocket which is previously unknown were identified by two fragments. Fragments that bind to this pocket were shown to inhibit the ATPase activity as well as the DNA topological transition activity of DNA gyrase in vitro. A set of fragment analogs were screened to explore the binding capacity of this pocket and identify the better starting fragments for lead development. Phylogenetic analysis revealed that this pocket is conserved in most Gram-negative and also many Gram-positive human pathogenic bacteria, implying a broad-spectrum antibacterial potential and a lower risk of mutation. Thus, the novel druggable pocket and the starting fragments provide a novel basis for designing new GyrB-targeting therapeutics.

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Publication details

The article was received on 16 Mar 2018, accepted on 03 Jul 2018 and first published on 04 Jul 2018

Article type: Research Article
DOI: 10.1039/C8MD00148K
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Identification of an auxiliary druggable pocket in DNA gyrase ATPase domain using fragment probes

    X. Huang, J. Guo, Q. Liu, Q. Gu, J. Xu and H. Zhou, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00148K

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