Transition state analogue inhibitors

Ubenimex, [(2(3),3(R))-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine, was isolated as an inhibitor of aminopeptidases, on which it acts as a strong, reversible transition-state analogue inhibitor (293). Analogues of ubenimex have been made and some other aminopeptidase inhibitors, not all of them peptides, have been isolated from streptomycetes (294—296). 

A Tropsha, J Hermans. Application of free energy simulations to the binding of a transition-state-analogue inhibitor to HIV protease. Protein Eng 51 29-34, 1992. 

Wolfenden, R., and Kati, W. M., 1991. Testing the limits of protein-ligand binding discrimination widi transition-state analogue inhibitors. Accounts of Chemical Research 24 209-215. 

Esler,W. P.,Kimberly,W.T.,Ostaszewski,B. L. etal.Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nature Cell Biol. 2 428-434,2000. 

Farrington, G.K., Kumar, A., and Wedler, F.C., Design and synthesis of new transition-state analogue inhibitors of aspartate transcarbamylase, /. Med. Chem., 28, 1668, 1985. 

V. L. Schramm and P. C. Tyler, Transition state analogue inhibitors of iV-ribosyltransferases, in P. Compain and O. R. Martin, (Eds.), Iminosugars From Synthesis to Therapeutic Applications, Wiley, Chichester, 2007, pp. 177-208. 

V. L. Schramm, and S. C. Almo, The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor, Biochemistry, 38 (1999) 9872-9880. 

V. Singh, W. Shi, G. B. Evans, P. C. Tyler, R. H. Fumeaux, S. C. Almo, and V. L. Schramm, Picomolar transition state analogue inhibitors of human 5 -methylthioadenosine phosphorylase and X-ray stmcture with MT-immucillin-A, Biochemistry, 43 (2004) 9-18. 

H.C. Wang, K. Kim, R. Bakhtiar, J.P. Germanas, Structure-activity studies of ground-and transition-state analogue inhibitors of cyclophilin, J. Med. Chem. 44 (2001) 2593-2600. 

Figure 3.24 Fluorinated ketones, transition state analogue inhibitor of chymotrypsin. ...

P. A. Bartlett and C. K. Marlowe, Phosphonamidates as transition-state analogue inhibitors of thermolysin, Biochemistry 1983, 22, 4618-4624. 

Oligopeptides containing the a-oxo-/ -amino amide moiety are useful transition-state analogue inhibitors of serine [25] and cysteine proteases [26], The a-hydroxy-... 

Kicska GA, Tyler PC, Evans GB, Furneaux RH, Kim K, Schramm VL (2002) Transition state analogue inhibitors of purine nucleoside phosphorylase from Plasmodium falciparum. J. Biol. Chem. 277 3219-3225... 

Evans GB, Furneaux RH, Lenz DH, Painter GF, Schramm VL, Singh V, Tyler PC (2005) Second generation transition state analogue inhibitors of human 5 -methylthioadenosine phosphorylase. J. Med. Chem. 48 4679- 1689... 

R. Wolfenden and W. M. Kati, Acc. Chem. Res., 24, 209 (1991). Testing the Limits of Protein-Ligand Binding Discrimination with Transition-State Analogue Inhibitors. 

Hanson JE, Kaplan AP, Bartlett PA. Phosphonate analogues of 63. earboxypeptidase A substrates are potent transition-state analogue inhibitors. Biochemistry 1989 28(15) 6294-6305. 

Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore 45. CL, Tsai J-Y, Rahmati T, Xia W, Selkoe DJ, Wolfe MS. Transition-state analogue inhibitors of y-secretase bind directly... 

Douglas KT, Nadvi IN. Inhibition of glyoxalase I A possible transition-state analogue inhibitor approach to potential antineo-plastic agents FEBS Lett. 1979 106 393-396. 

These extended-chain ketones are believed to interact with HLE similarity to the aldehyde and TFMK series of inhibitors. Although studies showing that they are true transition-state analogue inhibitors have not been reported, the formation of the covalent hemiketal adduct was documented in an X-ray crystallographic study of a DFK bound to PPE [150]. One notable finding is that the acidic N-terminal substituents first used by Trainor and co-workers to produce TFMKs with good in vivo profiles... 

Reactions such as acylation and deacylation are catalyzed by enzymes through lowering of the energy of activation. Binding and stabilization of the near tetrahedral oxyanion transition state by the active site of the enzyme is how this is accomplished. Thus, a transition state analogue inhibitor is a species, which binds the active site in a way similar to that... 

Inoue, M., Hiratake, J., and Sakata, K., Synthesis and characterization of intermediate and transition-state analogue inhibitors of y-glutamyl peptide ligases, Biosci. Biotechnol. Biochem., 63, 2248, 1999. 

---