Transition inhibitor design

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-... 

A recent example of the success of the bisubstrate, transition state design approach comes from the work of Pope and coworkers (Pope et al., 1998a-c Brown et al., 2000) on the design of inhibitors of bacterial isoleucyl tRNA synthetase... 

R. Wolfenden, Conformational Aspects of Inhibitor Design Enzyme-Substrate Interactions in the Transition State , Bioorg Med. Chem. 1999, 7, 647-652... 

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. 

KC Usher, LC Blaszczak, GS Weston, BK Shoichet, SJ Remington. Three-dimensional structure of AmpC (3-lactamase from Escherichia coli bound to a transition-state analogue possible implications for the oxyanion hypothesis and for inhibitor design. Biochemistry 37 16082-16092, 1998. 

Wolfenden R (1999) Conformational aspects of inhibitor design enzyme-substrate interactions in the transition state. Bioorg. Med. Chem. 7 647-652... 

Horenstein BA, Schramm VL (1993) ElecUonic nature of the transition state for nucleoside hydrolase. A blueprint for inhibitor design. Biochemistry 32 7089-7097... 

Thaisrivongs, S., Pals, D. T., Kroll, L. T., Turner, S. R., Han, F. S. Renin inhibitors. Design of angiotensinogen transition-state analogs containing novel (2R,3R,4R,5S)-5-amino-3,4-dihydroxy-2-isopropyl-7-methyloctanoic acid. J. Med. Chem. 1987, 30, 976-982. 

Enzymatic versus non-enzymatic transition states 241 The practice of TS analysis 242 TS analysis and inhibitor design 244 Mechanism nomenclature 244... 

From a biological perspective, one of the primary motivations for studying enzymatic mechanisms is inhibitor design. The relevance of the transition state to inhibitor design stems from the application of TS theory to catalysis, which states that enzymes catalyze reactions by binding tightly to the transition state in preference to any other species, thereby stabilizing Enzymes typically bind... 

Most HIV-PR inhibitor designs have focused on transition state analogues, i.e. analogues based on the known sequences of peptide substrates, but with the scissile bond replaced by a peptide bond isostere. Among the most effective peptide bond isosteres introduced into HIV-PR inhibitors have been the hydroxyethylene and hydroxyethyl-amine moieties (Fig. 20.7), in both of which the isosteric hydroxyl group is thought to mimic the tetrahedral... 

Chemical Reaction(s) Modeling and Design of Transition Inhibitors... 

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