The rational drug design is one of the major challenges in structural and
computational biology. Most of the known theoretical approaches on drug design
are based on knowledge of the structures of the biological targets and its active
sites where the drug binds. Such approaches use conventional force fields from
molecular dynamics simulations as well as empirical force fields derived from data
bases containing structures of different drugs bound to different targets where by
complex modelling procedures a drug molecule is built into the binding site of the
target molecule. The concept of indirect drug design tries to circumvent these
hurdles. This computational approach is suitable to model drugs, if the knowledge
on their binding sites is absent, assuming that drugs binding in the same pocket
have common properties, which can be elucidated by appropriate similarity
measures. Hence, by exploring the similarities between drugs that bind to the same
target, we may also obtain information on the conformation of the drug in the
binding pocket.
A detection of the three-dimensional binding mode between a protein and a
chemical compound is valuable to optimize drug candidates for high-throughput
screening. Pharmacophore models are essential functional groups of atoms in the
proper three-dimensional position to interact with a given receptor, and widely used
for drug design. Recent pharmacophore models can be classifed into two categories,
that are receptor-based pharmacophores and ligand-based pharmacophores. For a
receptor with a known three-dimensional structure, receptor-based
pharmacophores have been studied which are based on the famous concept of a key
for the lock .
On the other hand, since there are many proteins whose three-dimensional
structures have not been known, ligand-based pharmacophore models are still
useful. Traditionally, ligand-based pharmacophore models are computed by
extracting common features among three-dimensional structures of compounds
which are known to interact with a target protein
A protein kinase is a kinase enzyme that modifies other proteins by chemically
adding phosphate groups to them (phosphorylation). Phosphorylation usually results
in a functional change of the target protein (substrate) by changing enzyme activity,
cellular location, or association with other proteins. The human genome contains
about 500 protein kinase genes and they constitute about 2% of all human genes.
Protein kinases are also found in bacteria and plants. Up to 30% of all human
proteins may be modified by kinase activity, and kinases are known to regulate the
majority of cellular pathways, especially those involved in signal transduction .
The chemical activity of a kinase involves removing a phosphate group from ATP and
covalently attaching it to one of three amino acids that have a free hydroxyl group.
Most kinases act on both serine and threonine, others act on tyrosine, and a number
(dual-specificity kinases) act on all three. There are also protein kinases that
phosphorylate other amino acids, including histidine kinases that phosphorylate
histidine residues.
Receptor Tyrosine Kinases: The Main Targets for New Anticancer Therapy
Joachim Drevs, Michael Medinger, Carmen Schmidt-Gersbach, Renate Weber
and Clemens Unger
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Because conventional chemotherapy is not specific for cancer cells leading to
toxic side effects there is a need for novel agents with high grade antitumor
specificity. The major prerequisite to develop such drugs is to understand the
targets that these agents should attack. In recent years a number of promising
new anticancer drugs have been developed which target intracellular pathways
or extracellular cell molecules. The clinically most effective compounds function
as tyrosine kinase inhibitors. In the past, various tyrosine kinase receptors have
been identified as regulators of tumor or tumor vessel growth. Having shown
their expression characteristics in different tumor entities, specific inhibitors of
the ATP binding sites of these receptors or antibodies were developed and
entered clinical trials. The pathognomonic role of the tyrosine kinase defines the
way of action of the inhibiting drug, whereas the amount of expression in tumor
tissue defines the rationale to use the inhibitor to treat a specific protein. The
future will define indications for such drugs by tumor kinase profiles instead of
tumor entities. Gleevec, inhibiting the BCR-ABL tyrosine kinase; Iressa, inhibiting
the EGF-receptor tyrosine kinase; Herceptin, inhibiting the Her2/neu tyrosine
kinase and PTK787/ZK222584, inhibiting the VEGF-receptor tyrosine kinase will
be discussed as representatives of selective tyrosine kinase inhibitors whereas
ZD6474 and SU6668 will be discussed as representatives of multitarget tyrosine
kinase inhibitors.