title: 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.
abstract: 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.
authors.affiliation: Medivir AB, PO Box 1086, SE-141 22 Huddinge, Sweden. johan.isaksson@medivir.se
authors.forename: Johan
authors.initials: J
authors.lastname: Isaksson
authors.forename: Susanne
authors.initials: S
authors.lastname: Nyström
authors.forename: Dean
authors.initials: D
authors.lastname: Derbyshire
authors.forename: Hans
authors.initials: H
authors.lastname: Wallberg
authors.forename: Tatiana
authors.initials: T
authors.lastname: Agback
authors.forename: Helena
authors.initials: H
authors.lastname: Kovacs
authors.forename: Ivano
authors.initials: I
authors.lastname: Bertini
authors.forename: Andrea
authors.initials: A
authors.lastname: Giachetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Luchinat
mesh_terms: D018360:Crystallography, X-Ray; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D045726:Metalloproteases / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D008024:Ligands; D045726:Metalloproteases