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eHiTS: electronic High Throughput Screening
The flexible ligand docking problem is divided into two subproblems:
pose/conformation search and scoring function. For successful virtual
screening the search algorithm must be fast and able to find the
optimal binding pose and conformation of the ligand.
The presentation will demonstrate on practical examples
that algorithms employing stochastic elements or crude rotomer
samplings are unable to cover the search space with necessary
resolution.
eHiTS is an
exhaustive flexible docking method that systematically
covers the conformational and positional search space,
producing highly accurate docking poses at competitive
speed (few minutes per ligand). The sampling rate
of the systematic search can be controlled by parameters allowing fast
search (few seconds per ligand) while maintaining an accuracy level
comparable to results reached by other docking software that are slower.
The search
algorithm of eHiTS is based on exhaustive graph matching that rapidly
enumerates all possible mappings of geometric shape and chemical
feature graph of the ligand onto similar graph representation of the
receptor cavity. Dihedral angles of rotatable bonds are computed
deterministically as required by the positioning of the interacting
atoms. Consequently, the algorithm can find the optimal conformation
even if unusual rotomers are required.
eHiTS employs
a new scoring approach based on local surface point contact evaluation.
Surface point properties are
assigned with fine granularity: e.g. properties of
polar atoms in aromatic rings are different along
the edge and the faces of the ring. This overcomes the property
ambiguity problems inherent to atom based scoring functions. Receptor
surface points are also assigned pocket-depth information to express
differences in dielectric constants on solvated surface
points and deeply embedded cavity points.
Validation results of eHiTS on several hundreds of PDB complex
structures will be presented to demonstrate the ability of the program
to accurately reproduce known binding poses.
View full presentation.
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