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.
