Summary of Computational Chemistry Techniques Applied to Peptide Mimetic Design

SUMMARY OF COMPUTATIONAL CHEMISTRY TECHNIQUES APPLIED TO PEPTIDE MIMETIC DESIGN 

This chapter has presented many examples of the effective use of computational chemistry in peptide mimetic design. Clearly, computational chemistry can play a very useful role as part of the overall design process. A number of the peptidomimetics discussed here have been selected for further study as potential drug candidates or even reached the market.It therefore seems reasonable to claim that several of the case studies represent success stories in the application of computer-assisted molecular design (CAMD). This section briefly summarizes how computational chemistry techniques of different types 

Most researchers find it useful to employ three-dimensional graphics representations of peptides and proposed mimetics in their studies. This rudimentary level of molecular modeling allows for manipulation and geometric comparison of complex molecular structures. Using standard molecular bonding parameters, this level of analysis can test whether the proposed mimetic has the possibility of adopting the desired conformation, so that it can present important molecular recognition features in the appropriate orientation. 

Geometry optimization of the proposed mimetic is included as part of the design analysis to ensure the feasibility of the desired molecular conformation. MM and semiempirical quantum mechanical methods have been used most extensively for these purposes. Conformational analysis of the proposed mimetic allows the determination of an energy profile for the molecule under consideration. This has been used by researchers to assess where the desired conformation for the mimetic resides on the molecular potential energy surface. Monte Carlo, MD, and distance geometry-based conformational search techniques have been employed extensively to sample conformational space. Computational methods that attempt to approximate the efifects of aqueous solvation on the conformational profile of the mimetic are being used more frequently as part of these efforts. 

Comparison of the proposed mimetic with the peptide has taken on many levels of sophistication. Molecular overlays of low energy conformations of the mimetic and relevant conformations of the peptide have, in some cases, been performed based solely on visual inspection of the two structures. Sometimes there are many possible ways in which geometric correspondence between important recognition elements on the peptide and mimetic can be obtained. Computational methods that attempt to limit researcher prejudice in the overlap process by searching through the numerous possibilities have also been reported.i-55 159 Comparison of the relative electrostatic potential fields, the geometric location of specific recognition elements, and the overall molecular shape and steric volume have all been considered in these types of analyses. 

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