Biomedical Engineering Reference
In-Depth Information
series of seven-membered cyclic urea HIV-1 protease inhibitors (Figure 2.9E). Using the structural
information available from the many peptide-like inhibitors, the nature and stereochemistry of the
substituents on the cyclic urea could be designed so they were preorganized for binding to the
enzyme (Figure 2.10). By preorganization of a ligand for binding, the conformational energy pen-
alty, often associated with ligand binding, is reduced and the ligand may be more potent.
Although the DuPont Merck cyclic urea inhibitors were based on a brilliant structural idea and
potent inhibitors were designed, the inhibitors generally had low bioavailability and the HIV quickly
developed resistance against the compounds. Thus, none of these inhibitors are among the drugs
used today. Other companies have subsequently adopted the same idea in their design processes.
One example is the previously mentioned HIV-1 protease inhibitor tipranavir (Aptivus) where the
oxygen atom in the carbonyl group replaces the structural water molecule.
2.4 MEMBRANEPROTEINS
The largest group of biological targets for therapeutic intervention comprises the membrane proteins.
These proteins perform various functions in the cell, serving as enzymes, pumps, channels, trans-
porters, and receptors. To emphasize the importance of considering membrane proteins, ca. 40% of
all drugs target G-protein-coupled receptors.
The i rst membrane structure was reported in 1985 of the photosynthetic reaction center from
Rhodopseudomonas viridis
. Today, the number of known membrane protein structures is still
limited. Currently, the 3D structures are only known for 160 unique membrane protein structures
including proteins of the same type from different organisms (Membrane Proteins of Known 3D
Structure Web site, June 2008). The number of membrane protein structures and the change in
the number of structures as a function of time are similar to the state of soluble protein structures
approximately 25 years ago. The reason for this is primarily that expression, purii cation, and
crystallization of membrane proteins are still nontrivial and require substantial time and resources.
At the same time, structure determination of and biostructure-based drug design on membrane
proteins represent one of the most challenging areas of modern drug research.
Another strategy taken on membrane proteins is to produce soluble constructs of parts of the
proteins, e.g. the extracellular ligand-binding core of ionotropic glutamate receptors (iGluRs). These
receptors mediate most fast excitatory synaptic transmission within the central nervous system
(see Chapter 15). The glutamate receptors are not only involved in various aspects of normal brain
functions but are also implicated in a variety of brain disorders and diseases. Hence, iGluRs are
potential targets for biostructure-based drug design.
In 1998, the i rst structure of a ligand-binding core construct of an iGluR was reported, and
presently ca. 90 structures of iGluRs with bound glutamate, agonists, antagonists, or allosteric
modulators have been reported. The binding of ligands to the ligand-binding core of iGluRs can be
described as a “Venus l ytrap” mechanism. In the resting state the ligand-binding core is present in
an open form and it is this form that is stabilized by competitive antagonists (Figures 2.11 and 2.12).
When glutamate or an agonist binds to the ligand-binding core, a change in conformation occurs,
resulting in a closed form of the ligand-binding core. In full-length receptors, this domain closure
is thought to lead to the opening of the ion-channel (receptor activation). The presence of more than
one conformation of the ligand-binding core of iGluRs clearly stresses the importance of knowing
more than one structure of the receptor as fundament for biostructure-based drug design (for further
details on glutamate receptor structures, see Sections 1.3.2 and 12.2.2, and Chapter 15).
2.5 FAST-ACTINGINSULINS
Biostructure-based drug design is not limited to design of low-molecular weight compounds based
on knowledge of the structure of their biological targets. In the following text we are presenting an
example on biostructure-based design of macromolecular drug molecules, i.e., insulin analogs.
