Transition state isostere

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

Asp proteases Transition state isostere Statine, hydroxyethylamine 139, 140... 

A theoretical investigation of iV-methylmethanephosphonamidate (300), N-methylmethanephosphamide (302), and A-methylmethanesulfonamide (301) as protease transition-state isosteres has revealed that the anionic phosphonamidate (300) is the best mimic of the tetrahedral intermediate for base-catalysed A-methylacetamide (299) hydrolysis. " ... 

A third dataset was built in order to demonstrate that the descriptor is relevant for estimating binding affinity in a QSAR analysis. This last dataset contains 49 HIV-1 protease inhibitors, the 3D coordinates of which were those used by Pastor et al. (30). It has the four transition-state isosteres—hydroxy ethylene, hydroxyethylamine, statine, and a symmetrical diol. The X-ray structures of molecules numbered 1 and 3-34 have been reported (31), whereas molecules numbered 35-50 were modeled on the crystallographic structure of the complex of HIV-1 protease with L-689,502 solved at 2.25 A resolution (32). The binding affinity is expressed as pIC50 values. 

The presence of the additional p-carbon atom in Tau analogues offers the opportunity to study the influence of functionalization at this p-position as compared to functionalization at the a-position. Naturally occurring a-amino acids can be used as starting materials for the synthesis of homochiral P-substituted methylene sulfinamide and sulfonamide transition-state isosteres incorporated in peptides.11201... 

Moree, W. J., Schouten, A., Kroon, J., and Liskamp, R. M. J. (1995) Peptides containing the sulfonamide transition-state isostere synthesis and structure of N-acety 1 -tarvI -L-proline methylamide. Ini. J. Pept. Prot. Res. 45, 501-507. 

A class of HIV-l protease inhibitors extensively examined in our department are the cyclic sulfamides [73,74]. These compounds are related to our linear 1,2-dihydroxyethylene inhibitors described above in that they are also derived from L-mannitol and employ a 1,2-dihydroxyethylene transition-state isostere. These cyclic inhibitors are comprised of seven-membered rings where the sulfonyl oxygens are designed to displace a structural water in the enzyme when the inhibitors bind to the active site [73]. The synthesis of the... 

Figure 7 Various transition-state protease inhibitors. Bortezomib is an approved drug for the treatment of multiple myeloma. It is a boronic acid analog that inhibits the proteosome, a threonine protease. The boronic acid moiety can adopt a tetrahedral conformation in the active site. Pepstatin is a peptidyl aspartic acid inhibitor. The reactive statine group binds to the catalytic machinery, and the chiral hydroxyl group of the statine mimics the tetrahedral geometry of the transition state. Idinavir is an approved HIV 1 Protease inhibitor that binds to the active site via a hydroxyethylene transition state isostere. Aldehydes are also transition state analogs, which are susceptible to nucleophilic attack. In cysteine, serine and threonine proteases, this results in a covalent, reversible inhibition mechanism.

Workers at DuPont used a pharmacophore model and database search to develop the first type III mimetic inhibitor of HIV protease, DuP450 (87)(Fig. 15.38). This evolved from a 3D pharnacophorethat retained two key interactions replacement of the flap-bound water and a hydroxyl transition-state isostere (155). Molecular modeling led to a cyclohexanone as a better spacer between these groups, and finally the seven-membered cyclic urea (87) was created (Fig. 15.38). The development of these inhibitors illustrates the importance of conformational analysis in the design of constrained analogs. 

Transition state isostere Enzymes catalyze reactions by lowering the energy barrier that separates the substrate from the product. L. Pauling and others postulated that a substrate intermediate, the transition state, fits the enzyme better than both the substrate and the product, thereby favoring the conversion. This concept led to the design of enzyme inhibitors that resemble this transition state (bioisosteres) in order to better compete with the substrate, because of their higher affinity for the enzyme. 

US-FDA United States Food and Drug Administration TSl transition state isosteres... 

A common feature of nearly all X-ray crystal complexes between HIVPR and peptide-derived peptidomimetic inhibitors (PPIs) is the presence of a tetracoordinated structural water molecule tightly bound between the inhibitor molecule and the flexible beta strands or flaps of the HIVPR dimer. This ubiquitous water molecule accepts two hydrogen bonds from backbone amide bonds of flap residues IleSO and IleSO and donates two hydrogen bonds to suitable acceptors, typically carbonyl groups, which flank the transition state isostere of the peptide mimetic inhibitor (Fig. 3a) [31]. Potent... 

All the US-FDA approved Pis except Tipranavir (7) are substrate-based peptidic inhibitors. These inhibitors were designed using the "transition state peptidomimetic principle, which means that in the inhibitors the hydrolyzable peptide linkage is replaced by a non-hydrolyzable transition-state isostere (Fig. 11a) [158]. A munber of such isosteres were studied including statin, norstatin, hydroxyethylene, reduced amide, hydroxyethylamine, hydroxyethyl urea, monoalcohol, diol and aminodiols (Fig. 11b) [158]. Various classes of inhibitors containing dihydroxyethylene transition state isosteres were extensively developed. As an alternative to the peptide-based approach penicillin-derived C2 symmetric compounds were also pursued. 

Fig.11 a Hydrolysis of peptide linkage (Reprinted with permission from [158], Copyright 1995 American Chemical Society), b Some non-hydrolyzable transition state isosteres employed to replace the Pi-P j amide bond of the substrate for the design of HIVPl (Reprinted with permission from [158], Copyright 1995 American Chemical Society)... 

Many molecular modeUng and 3D-QSAR studies have been conducted on PPIs. In these studies a diverse dataset containing various classes of transition state isostere were used. It was difficult to group them according to different... 

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