Exploring the Sn binding pockets in gingipains by newly developed inhibitors: structure-based design, chemistry, and activity.

Abstract

Arg-gingipains (Rgps) and Lys-gingipain (Kgp) are cysteine proteinases secreted by Porphyromonas gingivalis, the major pathogen implicated in periodontal disease. Gingipains are essential to the bacterium for its virulence and survival, and development of inhibitors targeting these proteins provides an approach to treat periodontal diseases. Here, we present the first example of structure-based design of gingipains inhibitors, with the use of the crystal structure of RgpB and the homology model of Kgp. Chloromethyl ketones were selected as suitable compounds to explore the specificity of the Sn binding region of both enzymes. Three series of inhibitors bearing Arg or Lys at P1 and different substituents at P2 and P3 were designed, synthesized, and tested. High potency (k(obs)/[I] approximately 10(7) M(-1) s(-1)) was achieved for small ligands, such as the dipeptide analogues. The detailed analysis of Sn binding pockets revealed the molecular basis of inhibitory affinity and provided insight into the structure-activity relationship.

• Authors: Arkadiusz Białas, Jolanta Grembecka, Daniel Krowarsch, Jacek Otlewski, Jan Potempa, Artur Mucha
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 5 Pg. 1744-53 (Mar 09 2006) ISSN: 0022-2623 [Print] United States
• PMID: 16509589 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adhesins, Bacterial
• Amino Acid Chloromethyl Ketones
• Cysteine Proteinase Inhibitors
• Dipeptides
• Gingipain Cysteine Endopeptidases
• Cysteine Endopeptidases

Topics

• Adhesins, Bacterial (chemistry)
• Amino Acid Chloromethyl Ketones (chemistry)
• Amino Acid Sequence
• Binding Sites
• Crystallography, X-Ray
• Cysteine Endopeptidases (chemistry)
• Cysteine Proteinase Inhibitors (chemistry)
• Dipeptides (chemistry)
• Gingipain Cysteine Endopeptidases
• Models, Molecular
• Molecular Sequence Data
• Protein Conformation
• Sequence Homology, Amino Acid
• Structure-Activity Relationship
• Substrate Specificity