Abstract:
:Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology (LOGSY titration) that allows the determination of binding modes of low affinity binders in the protein-ligand interface and reveals suitable ligand positions for the addition of functional groups that either address or substitute protein-bound water, information of utmost importance for drug design. The particular benefit of the methodology and in contrast to conventional ligand-based methods is the independence of the molecular weight of the protein under study. The validity of the novel approach is demonstrated on two ligands interacting with bromodomain 1 of bromodomain containing protein 4, a prominent cancer target in pharmaceutical industry.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Geist L,Mayer M,Cockcroft XL,Wolkerstorfer B,Kessler D,Engelhardt H,McConnell DB,Konrat Rdoi
10.1021/acs.jmedchem.7b00845subject
Has Abstractpub_date
2017-11-09 00:00:00pages
8708-8715issue
21eissn
0022-2623issn
1520-4804journal_volume
60pub_type
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