Design of potent inhibitors for Schistosoma japonica glutathione S-transferase.
We implemented both structure-based drug design and the concept of polyvalency to discover a series of potent and unsymmetrical Schistosoma japonicum glutathione S-transferase (SjGST) inhibitors 10-12. This strategy achieved not only an excellent enhancement (10- to 490-fold) in the inhibitory potency, compared to the monofunctional analogues 1-5, but was also an effective modification by selecting a hydrophobic moiety with a flexible linker. The designed compounds with a low micromolar hit demonstrate special values in refining the new generation of SjGST inhibitors. The stoichiometry of the binding is one inhibitor molecule per SjGST monomer via isothermal titration calorimetric measurement.
Jao
Shu-Chuan
SC
Institute of Chemistry, Academia Sinica, Taipei 11529, Taiwan.
Chen
Jessica
J
Yang
Kelvin
K
Li
Wen-Shan
WS
D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012547:Schistosoma / Q000201:enzymology*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D017931:DNA Primers; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase