Proteins structural analogues, design

Table 8-1. Structures of LAP inhibitors, phosphinate dipeptide analogues, designed using LUDI. Experimental and predicted activities are presented for each compounds. a Value corresponding to the mixture of two diastereomers (1 1). Binding affinity for the mixture of four diastereomers. Value corresponding to the racemic mixture. Predicted binding affinity for one isomer which preferentially interacts with the protein...

An additional tool in structural analysis and analogue design has been TTR (formerly called T4 binding prealbumin), a plasma protein that binds as much as 27% of plasma T3 (107). The amino acid sequence of the TTR T3 binding site is known, and the protein has therefore served as a model, although admittedly an approximate model, for the T3 receptor. The TTR model portrays the T3 molecule as placed in an envelope... 

The molecular middle ground between nonheme di-iron enzymes and their small molecule synthetic analogues has been explored by de novo protein design. A protein can be designed to fold into a predetermined tertiary structure without patterning the sequence after any natural... 

On the one hand, the structure-based design of AChEIs is challenged by the large-amphtude fluctuations of the gorge structure and the fact that it contains more buried water molecules than a typical protein [40-42] on the other hand, this renders opportunities which could involve lycopodium alkaloids and their analogues as possible ligands for this enzyme. 

Transition state analogues are essentially stable molecules which resemble, in geometry and in charge distribution, metastable intermediates of the enzymic reaction. The actual transition state of the reaction will be close in structure to the metastable intermediate, and will quite likely vary slightly between different substrates accepted by the same enzyme. There will not be a unique transition state for all transformations catalysed by one particular enzyme, neither of course will there be a unique transition state for different enzymes catalysing the hydrolysis of peptide links in a protein. There will nevertheless be some similarities in mechanism, and so structures containing a tetrahedral centre have been designed to inhibit a variety of proteinases, where a tetrahedral intermediate is always presumed. Differences exist in the pathway to, and breakdown of, the tetrahedral intermediate, and its stabilization, between thiol and serine proteinases, zinc proteinases, and aspartic proteinases. 

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