Design and structure-based study of new potential FKBP12 inhibitors.
Based on the structure of FKBP12 complexed with FK506 or rapamycin, with computer-aided design, two neurotrophic ligands, (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-Leucine ethyl ester and (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester, were designed and synthesized. Fluorescence experiments were used to detect the binding affinity between FKBP12 and these two ligands. Complex structures of FKBP12 with these two ligands were obtained by x-ray crystallography. In comparing FKBP12-rapamycin complex and FKBP12-FK506 complex as well as FKBP12-GPI-1046 solution structure with these new complexes, significant volume and surface area effects and obvious contact changes were detected which are expected to cause their different binding energies-showing these two novel ligands will become more effective neuron regeneration drugs than GPI-1046, which is currently undergoing phase II clinical trail as a neurotrophic drug. Analysis of volume and surface area effects also gives a new clue for structure-based drug design.
Laboratory of Structural Biology, Tsinghua University, Beijing, China.
Fei
F
Sun
Pengyun
P
Li
Yi
Y
Ding
Liwei
L
Wang
Mark
M
Bartlam
Cuilin
C
Shu
Beifen
B
Shen
Hualiang
H
Jiang
Song
S
Li
Zihe
Z
Rao
D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry*; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D046911:Macromolecular Substances; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000737:chemistry; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000737:chemistry; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors* / Q000737:chemistry
D046911:Macromolecular Substances; D018696:Neuroprotective Agents; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus; D016559:Tacrolimus