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 specific biological functions. Thus, knowledge about such receptors or enzymes and the like in terms of their binding site for a ligand, and an understanding 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 conformation, but may be misleading in terms of function. Incorporation of these x-ray coordinates in to a computer-aided examination of a specific 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 affinity) so as to better understand the biological actions.

Peptide analogues that are sufficiently 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.

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