Biology Reference
In-Depth Information
5.3. Protein Design
Biotechnology often requires that proteins be redesigned to improve
their thermal stability 94 or solubility, 95 graft an epitope onto an immuno-
genic protein, 96,97 alter and optimize the binding properties of an anti-
body, 98-102 or change the substrate specificity of enzymes. 103 It is certainly
reasonable to consider that high-accuracy models can be used effectively
in protein redesign. However, one will have to carefully consider each
case, as every redesign project will have its own challenges.
5.4. Docking
Drug discovery and design are certainly one of the more desirable, but
demanding, applications of protein models. Early in the drug discovery
process, once a suitable drug target has been identified for a given dis-
ease, it is crucial to identify small molecules that bind to this target and
alter its activity (i.e. inhibition or activation). This is generally per-
formed by screening large collections of compounds in dedicated bio-
assays. The resulting “hits” can, if confirmed by one or more other relevant
biological assays, become the starting point of a compound optimiza-
tion process aimed at identifying highly efficacious analogs with low
toxicity. While compound screening is predominantly an experimental
approach, structure-based computational approaches provide an alter-
native and complementary way to identify such hits. In cases where
high-quality experimental 3D structures or models of the target protein
alone or in complex with a ligand are available, molecular docking
approaches can be used to simulate the nonbonded chemical interac-
tions between the target protein and individual compounds stored in
large libraries. 104
Notably, this approach is of particular interest when none or only
very few active compounds are available for a protein target. 105 There are,
however, many challenges in docking and drug design. For instance, the
ligand binding site on a protein structure can be very flexible and adopt
very different shapes, depending on ligand binding 106,107 ; conversely, the
conformation of the ligand itself can change upon binding. 108,109
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