Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase.
Sci Rep
; 9(1): 13587, 2019 09 19.
Article
de En
| MEDLINE
| ID: mdl-31537874
ABSTRACT
Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in silico inhibitor screening. The screening resulted in an active compound SH-5, the first nonpeptidyl inhibitor of S46 peptidases. SH-5 and a lipophilic analog of SH-5 showed a dose-dependent inhibitory effect against the growth of P. gingivalis. The binding mode of SH-5 was confirmed by crystal structure analysis. Thus, these compounds could be lead structures for the development of selective inhibitors of PgDPP11.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Benzoates
/
Porphyromonas gingivalis
/
Acide citrique
/
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Langue:
En
Journal:
Sci Rep
Année:
2019
Type de document:
Article
Pays d'affiliation:
Japon