Does a fast nuclear magnetic resonance spectroscopy- And X-ray crystallography hybrid approach provide reliable structural information of ligand-protein complexes? A case study of metalloproteinases

  • Isaksson J
  • Nystrom S
  • Derbyshire D
 et al. 
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A human matrix metalloproteinase (MMP) hydroxamic acid inhibitor (CGS27023A) was cross-docked into 15 MMP-12, MMP-13, MMP-9, and MMP-1 cocrystal structures. The aim was to validate a fast protocol for ligand binding conformation elucidation and to probe the feasibility of using inhibitor-protein NMR contacts to dock an inhibitor into related MMP crystal structures. Such an approach avoids full NMR structure elucidation, saving both spectrometer- and analysis time. We report here that for the studied MMPs, one can obtain docking results well within 1 A compared to the corresponding reference X-ray structure, using backbone amide contacts only. From the perspective of the pharmaceutical industry, these results are relevant for the binding studies of inhibitor series to a common target and have the potential advantage of obtaining information on protein-inhibitor complexes that are difficult to crystallize.

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  • Johan Isaksson

  • Susanne Nystrom

  • Dean Derbyshire

  • Hans Wallberg

  • Tatiana Agback

  • Helena Kovacs

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