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Issue 3, 2014
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Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

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Abstract

An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the complex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.

Graphical abstract: Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

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Publication details

The article was received on 30 Sep 2013, accepted on 11 Nov 2013 and first published on 26 Nov 2013


Article type: Paper
DOI: 10.1039/C3OB41975D
Citation: Org. Biomol. Chem., 2014,12, 486-494
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    Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

    M. Fisher, R. Basak, A. P. Kalverda, C. W. G. Fishwick, W. Bruce Turnbull and A. Nelson, Org. Biomol. Chem., 2014, 12, 486
    DOI: 10.1039/C3OB41975D

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