Design Considerations

The paradigm that underlies biological active peptides and peptidomimetics drug design can broadly be considered as ligand-based drug design and receptor/acceptor biological activity-based drug design (Figure 8.2).

For GPCRs, cytokine receptors, and the like, endogenous ligands have affinity for the extracellular region of the receptor, binding to a specific region of the receptor. For GPCRs, a ligand whose binding causes a measurable increase in basal activity of second messengers is defined as an agonist. A ligand that interacts with the receptor in the same binding pocket and causes no

Ligand-based design Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Ar-Trp-Gly-Lys-Pro-Val-NH2 (a-MSH) i ; ; Based on ligand similarity

| j • Truncation ; ; I • Amino acid scan I ; ; • Scaffold, fragment,

| ; chemotype, pharmacophore

♦ ; • Conformational constraint ; • p-Turn peptidomimetics I • 3D structure of ligand (NMR, x-ray)

♦ ; • Conformational constraint ; • p-Turn peptidomimetics I • 3D structure of ligand (NMR, x-ray)

Receptor/acceptor-based design Based on the similarity of receptor/acceptor

• Receptor class (e.g., GPCR); overall sequence homology (phylogenetic tree)

• Multiple site directed mutagenesis

• Domain shift or chimeric receptors

• 3D structure of binding site

• Cell functional response (signaling pathway)

Receptor/acceptor-based design Based on the similarity of receptor/acceptor

• Receptor class (e.g., GPCR); overall sequence homology (phylogenetic tree)

• Multiple site directed mutagenesis

• Domain shift or chimeric receptors

• 3D structure of binding site

• Cell functional response (signaling pathway)

FIGURE 8.2 Design of biologically active peptides and peptidomimetics.

change in the basal activity of the second messenger functions is defined as a neutral competitive antagonist. A ligand that interacts with the receptor in the same binding pocket and causes the biological activity below the basal level is defined as inverse-agonist. Agonists and antagonists are of vital significance in drug design for targeting specific diseases. For example, a potent and selective agonist toward human melanocortin receptor 4 (hMC4R) may be important for the treatment of obesity. Development of antagonists may be critical in the areas of addiction and tolerance, which are generally induced by prolonged use of opiates. Thus, designing of agonists, antagonists, and inverse-agonist is of utmost importance depending on the targets. Such design can be based on two broad categories; (1) ligand-based; and (2) receptor/acceptor-based design (Figure 8.2). Although design of agonists and antagonists share some common strategies, at some point they must diverge due to their different biological effects. We will discuss here some common approaches toward the design of biological active peptides.

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