Biomedical Engineering Reference
In-Depth Information
Ligand-based
design
Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Ar-Trp-Gly-Lys-Pro-Val-NH
2
(α-MSH)
Based
• Truncation
•
Amino acid scan
•
Scafold, fragment,
chemotype, pharmacophore
•
Conformational constraint
•
β-Turn peptidomimetics
•
3D structure of ligand (NMR, x-ray)
•
Computational-aided drug design
on ligand
similarity
H
2
N
O
NH
NH
HN
O
HN
O
O
O
HN
O
HN
O
NH
NH
N
O
NH
O
N
N
N
O
H
N
O
N
NH
HN
NH
Cl
NH
2
Nonpeptide mimetic
Peptidomimetic: MTII
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 dei ned as a neutral competitive
antagonist. A ligand that interacts with the receptor in the same binding pocket and causes the bio-
logical activity below the basal level is dei ned as inverse-agonist. Agonists and antagonists are of
vital signii cance in drug design for targeting specii c 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.
8.3.1 L
IGAND
-B
ASED
D
ESIGN
The ligand is a natural peptide whose structure/sequence is known (a natural endogenous peptide
hormone or neurotransmitter) or discovered by combinatorial chemistry, biology, or through pro-
teomic strategies/identii cation.
