Transition state mimic

Many examples exist of potent enzyme inhibitors that function as transition state mimics (see Chapter 7 Schramm, 1998, and Wolfenden, 1999, for some examples). An understanding of the transition state structure is thus of great valuable for inhibitor design. As described in Chapter 1, the transition state is not the only inter-... 

Figure 7.9 Chemical structures of ligands of the enzyme PNP. (A) The substrate inosine, (B) the inosine and phosphate transition state, and (C) the transition state mimic inhibitor Imucillin H.

Figure 14-9. Snapshots from the simulations of the early transition state mimic (left) and the late transition state mimic (right), indicating the Mg2+ ion direct coordination (green lines) and key hydrogen bonds and indirect Mg2+ coordination (dotted lines). For clarity, the water molecules are not shown...

The incorporation of an ionizable center, such as an amine or similar function, into a template can bring a number of benefits, including water solubility. A key step in the discovery of the protease inhibitor, indinavir was the incorporation of a basic amine (and a pyridine) into the backbone of hydroxyethylene transition state mimic compounds L-685,434 to enhance solubility (and potency) (Fig. 1.2) [17]. 

A similar bait and switch approach has been exploited for acyl-transfer reactions (Janda et al., 1990b, 1991c). The design of hapten [10] incorporates both a transition state mimic and the cationic pyridinium moiety, designed to induce the presence of a potential general acid/base or nucleophilic amino acid residue in the combining site, able to assist in catalysis of the hydrolysis of substrate [11] (Appendix entry 2.6). 

Moving closer to a cationic transition state mimic, Hasserodt et al. (1996) used the amidinium ion [75] as a TSA for cyclization of the arenesulfonate ester [761- One antibody raised to this hapten, 17G8, catalysed the conversion of substrate [76] into a mixture of the 1,6-dimethylcyclohexene [77] and 2 methylene-1-methylcyclohexane [78] (Fig. 28) (Appendix entry 15.3). By contrast the uncatalysed cyclization of [76] formed a mixture of 1,2-... 

The vanadium oxide V04 [conjugate base of the acid V03(0H) ] that adopts trigonal bipyramidal geometry and acts as a transition-state mimic for in-hne phosphoryl transfer enzymes. See Oxygen, Oxides, Oxo Anions... 

PROTON INVENTORY TECHNIQUE Transition-state mimic,... 

Davies, D. R., Interthal, H., Champoux, J. J. and Hoi, W. G.J. (2003). Crystal structure of a transition state mimic for Tdpl assembled from vanadate, DNA, and a topoi-somerase 1-derived peptide. Chem. Biol. 10,139-147. 

S. G. Withers, M. Namchuk, and R. Mosi, Potent glycosidase inhibitors Transition state mimics or simply fortuitous binders in A. E. Stiitz (Ed.), Iminosugars as Glycosidase Inhibitors, Wiley-VCH, Weinheim, New York, 1999, pp. 188-206. 

M. Hrmova, R. de Gori, B. J. Smith, A. Vasella, J. N. Varghese, and G. B. Fincher, Three-dimensional structure of the barley p-D-glucan glucohydrolase in complex with a transition state mimic, J. Biol. Chem., 279 (2004) 4970 1980. 

The statine-like moiety in one of the first drugs, saquinovir (23-8), comprises a transition state mimic for the cleavage of phenylalanylprolyl and tyrosylprolyl sequences. Constmction starts with the protection of the amino group of phenylalanine as its phthaloyl derivative (Phth) by reaction with phthalic anhydride this is then converted to acid chloride. The chain is then extended by one carbon using a Friedel-Crafts-like reaction. The required reagent (21-2) is prepared by reaction of the enolate obtained from the /7A-silyl ether (21-3) of glyoxylic acid and lithio... 

The discovery of yet other nonhydrolyzable amide bond isosteres has particularly impacted the design of protease inhibitors, and these include hydroxymethylene or FfCF OH)], 12 hydroxyethylene or T fCF OFQCFy and T fCFkCHiOH)], 13 and 14, respectively dihydroxyethylene or ( [ )], 15, hydroxyethylamine or 4 [CH(0H)CH2N], 16, dihydroxyethylene 17 and C2-symmetric hydroxymethylene 18. In the specific case of aspartyl protease inhibitor design (see below) such backbone modifications have been extremely effective, as they may represent transition state mimics or bioisosteres of the hypothetical tetrahedral intermediate (e.g., xF[C(OH)2NH] for this class of proteolytic enzymes. 

Transition state mimics have generally been synthesized first on an empirical basis tetrahedral analogues if the mechanism involves a tetrahedral intermediate planar analogues if the enzyme catalyses an SNl displacement, as exemplified by the synthesis of DANA (71) for the inhibition of neuraminidase. Recognition that transition state geometry and... 

Gil-Ortiz, E Ramon-Maiques, S. Fita, L Rubio, V. The course of phosphorus in the reaction of N-acetyl-L-glutamate kinase, determined from the structures of crystalline complexes, including a complex with an AlF(4)(-) transition state mimic. J. Mol. Biol., 331, 231-244 (2003)... 

A similar strategy was used to examine the potential role of a reverse turn as a recognition element adjacent to the cleavage site of substrates of HIV protease.197 A series of inhibitors was prepared, the synthesis of which involved the solution coupling of the statine-like transition state mimic to the (3-turn mimetic to provide 46 (Scheme 22). Subsequent sodium in ammonia reduction provided analogue 47. One of the compounds was a reasonably potent inhibitor of protease activity (IC50=2.6 x 10-8 M) (Table 1). 

Peptidyl fluoromethyl ketones are widely used as fairly potent inhibitors for a variety of proteases, including serine, cysteine, and aspartyl proteases. Unlike other halomethyl ketones (Section 15.1.3), fluoromethyl ketones are reversible transition-state mimics. The electron-withdrawing fluorine(s) next to the carbonyl group enhances the electrophilicity of the a-fluoroalkyl ketone functionality, thereby making the carbonyl more susceptible to nucleophilic attack. a-Fluoroalkyl ketones are good mimics of peptide bonds due to the small size of the fluorine and the stability of C F bonds. There are three general classes of peptidyl fluoromethyl ketones fluoromethyl ketones (irreversible inhibitors of cysteine proteases), difluoromethyl ketones (reversible inhibitors of both serine and aspartyl proteases), and trifluoromethyl/perfluoroalkyl ketones, which typically exist in hydrated forms and are excellent inhibitors of both serine and cysteine proteasesJ1 ... 

Antibodies were generated against a bent A-alky 1 mesoporpbyrin, which is a known inhibitor of the enzyme ferrochelatase. Ferrochelatase catalyzes the insertion of Fe(II) into protoporphyrin, as part of the heme biosynthetic pathway (Lavallee, 1988). Antibody 7G12 was found to catalyze the insertion of divalent metal ions into porphyrins, with a rate similar to thatfound for ferrochelatase (Cochran and Schultz, 1990). The structural data presented below supports the hypothesis that the transition state for porphyrin metallation involves a distortion of the macrocyclic ring system to facilitate metal insertion, and that this bent porphyrin acts as a good transition-state mimic in the development of catalytic antibody 7G12. 

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