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