The Discovery of MMP7 Inhibitors Exploiting a Novel Selectivity Trigger

• Published in: ChemMedChem Vol. 6; no. 5; pp. 769 - 773
• Main Authors: Edman, Karl, Furber, Mark, Hemsley, Paul, Johansson, Cristian, Pairaudeau, Garry, Petersen, Jens, Stocks, Michael, Tervo, Anu, Ward, Alison, Wells, Edward, Wissler, Lisa
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 02.05.2011; WILEY‐VCH Verlag
• Subjects: Amino Acid Sequence; Binding Sites; biological activity; Catalytic Domain; Computer Simulation; Crystallography, X-Ray; drug discovery; Drug Evaluation, Preclinical; High-Throughput Screening Assays; inhibitors; Matrix Metalloproteinase 7 - metabolism; Matrix Metalloproteinase Inhibitors; medicinal chemistry; Molecular Sequence Data; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Sequence Alignment; X-ray diffraction
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000550

Trigger happy! High‐throughput screening was used to identify selective MMP7 inhibitors. Subsequent analysis by X‐ray crystallography revealed the underlying features for the selectivity trigger, unique to MMP7. In addition, further structural studies increased the understanding of the plasticity of the MMP7 active site. Finally, a single round of chemistry resulted in compounds with improved potency and retained selectivity.