Applying Computational and Biophysical Studies for Design

Rational design should be and is currently a central theme for drug discovery. Experimental and theoretical developments in peptide chemistry and biophysical methods, in conjunction with new biological methods have offered a wide variety of new design, synthesis, and analysis methods for

Peptide linear presentation of pharmacophore

Peptide linear presentation of pharmacophore

Peptide turn presentation of pharmacophore

Peptide 3D presentation of pharmacophore

Peptide turn presentation of pharmacophore

Peptide 3D presentation of pharmacophore

FIGURE 8.8 Peptide structures to mimic in peptide mimetic design.

FIGURE 8.9 NMR structures of superimposed MTII (green) and SHU9119 (yellow) (left) and NMR structure of AGRP (right).

peptides with powerful biological properties. The use of computational methods in conjunction with molecular modeling is a powerful tool in design considerations, with the caveat that for novel structures, current force fields might not give an accurate picture of the structure or energetics of the system. As an example of melanocortin system, along with the nuclear magnetic resonance (NMR) structure of Agouti-related protein (AGRP, an endogenous antagonist of hMC3R and hMC4R) and MTII (superagonist of hMC4R), the 3D pharmacophore of human melanotropin has been partially deciphered (Figure 8.9). The primary structure of both MTII and AGRP are quite different, but from their NMR it can be found that they both share the same P-turn like structure. These accomplishments combined with the computational chemistry can be very crucial for designing novel selective agonist and antagonist compounds.

There is one computational approach for mapping molecular interaction space without knowledge of the 3D structure, known as proteochemometrics. It is an extension of traditional ligand-based 3D QSAR approaches. It exploits affinity data for a series of diverse organic ligands binding to different receptor subtypes, providing proteochemometric analysis, and insights into ligand recognition.

8.3.2 Design Based on the Biological Function

The paradigm that underlies the chemogenomics approaches to ligand design can be stated as "similar receptor/acceptor binds similar ligand." This implies that for a novel receptor/acceptor, the 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 insufficient 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.

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