Bisubstrate inhibitors

If we are able to covalently link these two compounds together in a way that captures all their individual binding interactions, the free energy of binding for the bisubstrate inhibitor will be the sum of the free energies of the individual molecules that is, the free energy, assuming no loses of productive interactions, will be -14.4 kcal/mol. The Kt of this combined, bisubstrate inhibitor will therefore be... 

Figure 7.10 Chemical structure of SB-234764, a tight binding bisubstrate inhibitor of bacterial isoleucine tRNA synthetase.

Over the past decade, however, the PTK inhibitors favored by most investigators have been ATP mimics that compete with ATP at the binding site. Most of the compounds depicted in Table 2 are ATP mimics with the exception of the tyrphostins developed by us. In the case of tyrphostins one can indeed classify compounds which compete with ATP, compounds which compete with the substrate and bisubstrate inhibitors which compete with the substrate and ATP simultaneously [18]. Compounds can also be identified that act as mixed competitive inhibitors which bind simultaneously with ATP and/or substrate but decrease the affinity of ATP and the substrate to their respective sites [18,22]. Among the tyrphostins all classes of compounds can be identified [18] but the real question is which of these is preferable for clinical development. 

However, bisubstrate inhibitors incorporating a farnesyl- and a CAAX mimetic are very promising since one can expect that they display enhanced... 

Figure 9. P-Thioglycinamide ribonucleotide dideazafolate a typical bisubstrate inhibitor.

In practice, these considerations usually reduce A G si,- i er by > three orders of magnitude (> — 4 kcal mol-1) since observed effective concentrations > 105 M are rarely if ever seen in bisubstrate inhibitors. For example, N-phosphonoacetyl-L-aspartate (PALA),1241 in clinical trials in the 1980s, is a typical bisubstrate analog1251 with Kt = 27 nM (Fig. 11) and an observed effective concentration of > 17 M (equa-... 

Figure 11 PALA a bisubstrate inhibitor that reached clinical trials.

Cole, P.A. and Marmorstein, R. (2002) Structure of the GCN5 histone acetyltransferase bound to a bisubstrate inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 99 (22), 14065—14070. 

Thutewohl M, Kissau L, Popkirova B, Karaguni I-M, Nowak T, Bate M, Kuhlmann J, Miiller O, Waldmann H (2003) Identification of Mono- and Bisubstrate Inhibitors of Protein Famesyltransferase and Inducers of Apoptosis from a Pepticinnamin E Library. Bioorg Med Chem 11 2617... 

Fig. 9.1. Small molecule inhibitors of Reel (A) A-Boc-farnesylated tetrapeptide, (B) BFCCMK, (C) a bisubstrate inhibitor.

L. M. McDowell, D. R. Studelska, B. Poliks, R. D. O Connor and J. Schaefer, Characterization of the complex of a trifluoromethyl-substituted shikimate-based bisubstrate inhibitor and 5-enolpyruvylshiki-mate-3-phosphate synthase by REDOR NMR. Biochemistry, 2004, 43, 6606-6611. 

FIGURE 18.40 (a) Interaction of the bisubstrate inhibitor RM65 (magenta) and SAM (green) with the PRMTl binding site. The symmetrical inhibitor... 

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