eHiTS (electronic High Throughput Screening): New method for fast, exhaustive flexible ligand docking

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 full search space with necessary resolution to reproduce experimentally observed binding geometries.

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.