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

作者：Isaksson Johan^*; Nystom Susanne; Derbyshire Dean; Wallberg Hans; Agback Tatiana; Kovacs Helena; Bertini Ivano; Giachetti Andrea; Luchinat Claudio

来源：Journal of Medicinal Chemistry, 2009, 52(6): 1712-1722.

DOI：10.1021/jm801388q

A human matrix metalloproteinase (NIMP) 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 angstrom 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.

• 出版日期2009-3-26