enzyme inhibitors that prolong the effective half-life of remaining acetylcholine
molecules within the brain.
As discussed in chapter 1, the human body contains many different molecules and thus
offers many opportunities for the discovery of lead compounds based on endogenous
molecules. Nowhere is this opportunity more apparent than in the area of peptide neu-
rotransmitters and peptide hormones (see chapters 4 and 5). Neurotransmitters and hor-
mones are endogenous messengers, controlling diverse biochemical processes within
the body. Not surprisingly, they have the capacity to be ideal starting points in the drug
discovery process. However, there are a number of major problems that must be con-
fronted when exploiting peptides or proteins as lead compounds for drug discovery.
Peptidomimetic chemistry is an attempt to address these problems.
3.2.3.1 Peptidomimetic Chemistry as a Source of Lead Compounds
Although they are potent endogenous bioactive molecules, peptides rarely make good
drugs. There are several reasons for the failings of peptides as drugs:
- Peptides are too big (molecular weight frequently over 1000 dalton).
- Peptides are often too flexible (thus binding with too many receptors, leading to
toxicity). - Peptides contain amide bonds that can be metabolized by hydrolysis.
- Peptides cannot be given orally as drugs (they tend to be digested).
- Peptides do not readily cross the blood–brain barrier to enter the brain.
Despite these obvious deficiencies, peptides have a number of properties that make
them attractive as starting points in drug design:
- Peptides contain numerous stereogenic (chiral) centers (an excellent starting point
when designing stereoselective drugs). - Peptides contain many functional groups (e.g., carboxylate, ammonium, hydroxyl,
thiol) that can readily constitute functional groups within a pharmacophore; since
receptors are usually proteins, peptides are good starting points for designing a
molecule to interact with a receptor, owing to the energetically favorable nature of
peptide–peptide interactions. - Peptides are easily synthesized and many analogs can be readily produced.
- Peptides can have their conformation and geometries easily optimized by energy
minimization calculations using current computational methods (e.g., molecular
mechanics); this makes subsequent modeling studies easy. - Peptides function as neurotransmitters and hormones and thus are good starting
materials when designing bioactive molecules.
Since peptides are ideal starting molecules that cannot be turned into successful peptidic
drugs, the specialty area of peptidomimetic chemistry has emerged. The goal of pep-
tidomimetic chemistry is to design small, conformationally constrained, non-peptidic
organic molecules that possess the biological properties of a peptide. Hopefully, this will
retain the strength of the peptide as a putative drug while eliminating the problems. There
are two approaches whereby peptidomimetic chemistry can achieve this design goal.
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 113