Аннотация
In recent years there has been a growing interest in computer-based
screening. One of the driving forces has been the increased efficiency
of protein crystallography leading to the real possibility of using
structure-based design as a significant contributor to the discovery
of novel ligands. In 1957 after 22 years of work the first protein
structure, determined by x-ray crystallography was produced 1.
Now the process has become increasingly automated and nearly 20,000
protein structures are available in the Protein Data Bank (PDB) 2.
Equally, progress in genomics will result in a great expansion of
validated targets for cancer therapy. The understanding of the relationships
between structure and function of gene products will be one of the
key routes to new therapeutic advances. The challenge now is to use
this data in the discovery of novel therapeutics. One approach is
obviously to synthesize molecules and co-crystallize or soak them
into the protein crystal and so determine the position and interaction
of the molecule with the protein. The structural information obtained
(where does the molecule bind; what are the ligand/protein/solvent
interactions?) can be invaluable in the generation of novel molecules
or in the re-design of existing molecules whose drug properties are
not optimal. However, when dealing with large numbers (millions)
of molecules, when crystallization is difficult or in testing hypotheses,
a significant contribution can be made using computer based screening
methods. In order to use the structural information derived from
x-ray crystallography (or other sources, for example NMR or homology
modelling) when evaluating the utility of a novel ligand, we need
to understand where in the protein (or other macromolecule such as
RNA) the ligand is likely to bind and also if possible, the strength
of the binding interactions. This problem is known as the 'docking
problem'. There have been many approaches to the solution of this
problem over the last ten years. For example, some methods rely on
complex molecular dynamics simulations while others use less costly
graph matching approaches. There is generally a compromise between
speed and accuracy, with some methods giving much more information
and insight into the nature of the protein/ligand interactions and
other methods optimised for speed of docking thousands of putative
ligands. We will describe some of the more common methods and algorithms
used to solve the docking problem and in particular, we will review
recent applications in cancer research.
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