Peptides and Peptidomimetics - Drug Design and Discovery

Biomedical Engineering Reference

In-Depth Information

information obtained from a known ligand for a related receptor/acceptor, can serve as a starting

point for ligand design. Proteins that belong to the same target family or class (e.g., the family of

GPCRs) can be considered as similar. Although all GPCRs have seven transmembrane helices and

translate an extracellular signal into an intracellular response mediated by G proteins, there is a

great diversity of ligands for GPCRs. Moreover, there is currently insufi cient reliable 3D structural

information available regarding the GPCRs. Thus, insights into ligand-receptor interactions have

to rely on molecular recognition experiments. Multiple site-directed mutagenesis have been used to

identify the ligand-binding site as well as the biological function site. Recently, domain shift or chimeric

receptors also have been used to provide information about the binding domain for a ligand.

8.4 MODELING AND DOCKING

In this chapter, we have emphasized that a peptide or endogenous ligand in a biological system upon

interaction with an enzyme or GPCR leads to specii c biological functions. Thus, knowledge about

such receptors or enzymes and the like in terms of their binding site for a ligand, and an under-

standing of the bound ligand-receptor complex is of utmost importance. A critical approach to

understand receptor structure is its orientation in 3D space. X-ray crystal structures provide 3D con-

formation, but may be misleading in terms of function. Incorporation of these x-ray coordinates in

to a computer-aided examination of a specii c function in 3D space is being pursued. This allows to

further explore the region/site or the surrounding 3D space occupied by the key amino acids of the

protein (where the potent ligand has an afi nity) so as to better understand the biological actions.

Peptide analogues that are sufi ciently constrained, whose conformational and dynamic properties

are known from multidimensional NMR and other spectroscopic methods, in combination with

modern molecular mechanics methods and docking experiments can greatly aid peptide ligand

development. Exploring the accessible conformational space on the docking site of the receptor/

acceptor serves as the starting point for further design of analogues to develop conformation-biological

activity relationships. Such molecular modeling studies provide a useful tool toward the generation

of potent peptide or peptidomimetics ligand structures. Docking for the enzyme-based proteins are

widely available because the x-ray structures are available in many cases. Unfortunately, the same is

not true for GPCRs and many other proteins, especially integral membrane proteins. In these cases,

homology modeling with the few known structures in these classes has been somewhat successful,

but further developments are still required.

8.5 CONCLUSIONS

The design of peptides and peptidomimetics is often the i rst step of drug discovery. To obtain a use-

ful peptide or peptide mimetics drug requires a multidisciplinary approach including chemical biol-

ogy, biophysics, and biological approaches. It is necessary to be aware of all available information

and design methods in order to begin such a drug discovery program. Several chemical, biophysical,

and bioinformatics approaches have been discussed and need to be evaluated in conjunction with

the results from the best possible and appropriate in vitro and in vivo assays. This multidisciplinary

approach will be essential for the development of rational approaches to peptide-based drug design

in the future.