Improving specificity vs bacterial thymidylate synthases through N-dansyl modulation of didansyltyrosine.
N,O-Didansyl-L-tyrosine (DDT) represented the starting lead for further development of novel non-substrate-like inhibitors of bacterial thymidylate synthase. The N-dansyl structure modulation led to a submicromolar inhibitor of Lactobacillus casei TS (LcTS), which is highly specific with respect to human TS (hTS). Using molecular dynamics simulation, a binding mode for DDT vs LcTS was predicted, explaining activity and species-specificity along the series.
Tondi
Donatella
D
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy. tondid@unimore.it
Venturelli
Alberto
A
Ferrari
Stefania
S
Ghelli
Stefano
S
Costi
M Paola
MP
D001419:Bacteria / Q000201:enzymology*; D003619:Dansyl Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007780:Lacticaseibacillus casei / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*
D003619:Dansyl Compounds; C446819:N,O-didansyl-L-tyrosine; D014443:Tyrosine; D013940:Thymidylate Synthase