Matrix metalloproteinase target family landscape: a chemometrical approach to ligand selectivity based on protein binding site analysis.
To gain insight into the structural determinants for the matrix metalloproteinase (MMP) family, we characterized the binding sites of 56 MMP structures and one TACE (tumor necrosis factor alpha converting enzyme) structure using molecular interaction fields (MIFs). These MIFs were produced by two approaches: the GRID force field and the knowledge-based potential DrugScore. The subsequent statistical analysis using consensus principal component analysis (CPCA) for the entire binding site and each subpockets revealed both approaches to encode similar information about discriminating regions. However, the relative importance of the probes varied between both approaches. The CPCA models provided the following ranking of the six subpockets based on the opportunity for selective interactions with different MMPs: S1' > S2, S3, S3' > S1, S2'. The interpretation of these models agreed with experimental binding modes inferred from crystal structures or docking.
Pirard
Bernard
B
Science and Medical Affairs, Chemical Sciences, Drug Design, Aventis Pharma Deutschland GmbH, a Company of the Sanofi-Aventis Group, D-65926 Frankfurt am Main, Germany. bernard.pirard@novartis.com
Matter
Hans
H
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D000072198:ADAM17 Protein; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000145:classification; D008958:Models, Molecular; D015394:Molecular Structure; D025341:Principal Component Analysis; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human