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Can we trust docking results?
Sept 2010 IBM Systems and Technology Group releases a white paper with eHiTS and Cell
Oct 2008
EPA's ToxCastTM project will use SimBioSys' eHiTS as docking engine
Nov, 2007
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| 243rd ACS
Mar 25-29, 2012
San Diego, CA
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Methods
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The sections below provides some descriptions
of the methods within the different SPROUT modules, as well as links to other pages containing much more detail. |
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Presently, it is impossible to think about chemical modelling without computer graphics. A 3D graphical visualisation tool has been developed in SPROUT to display the detected interaction site regions, and the generated chemical structures together with the protein receptor and boundary surface. SPROUT's ability to visualize the protein-ligand interactions is unmatched and many use SPROUT sometimes for this purpose alone.
Further details on SPROUT's visualizations can be found here.
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Cleft detection is performed in SPROUT by the CANGAROO module. A cleft is defined within the program as a large inward facing area on the surface of the protein. This definition is purely based on geometry. This surface (VDW, Connolly, solvent accessible, etc) is composed of a set of points computed at a given density (generally between 1 and 3 points/�^2). A special kind of surface curvature is calculated for each point of the surface. The curvature's normal vectors are computed and orientated towards the inside of the surface if the region around the current point is inward-facing and directed outwards should the region be outward-facing. A simple clustering of the points according to their curvature, normal direction and their relative position in space, gives a set of inward-facing areas.
Further details on the molecular surfaces and their curvatures can be found here.
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Target site representation, as performed by the HIPPO module, is a rule based approach. Typical donor and acceptor atoms are located in the protein, intramolecular hydrogen bonds are identified, hydrogen bonding atoms near to the surface of the receptor site are found, and finally hydrogen bonding regions are computed for them with tolerances. Of note, metal ions and residue motifs, like the SER-HIS-ASP triad, that tend to form covalent bonds to ligands, are also identified and the appropriate target sites are generated.
Once the ideal bond has been computed, tolerances are applied to both the distance and the direction so that a target site is defined by a geometric region rather than as a single point or a grid.
Further details on target site idenfication and representation can be found here.
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Before structure generation can begin, a set of target sites, a steric boundary and a set of start structure templates are required. The ELEFANT module is designed to select and orientate the start templates representing functional groups at each of the selected target sites. The functional group selection is based on the information provided by HIPPO and takes into account the distances, relative postions and directions of those target sites which are close to each other.
Further information regarding start template docking can be found here, as well as the second part of this paper.
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The SPIDER module generates skeletons that satisfy the initial constraints of a binding pocket. This is done by positioning spacer fragments onto the start fragments and then connecting the resulting part skeletons together.
The initial constraints consist of a set of target sites, a steric boundary, a set of parameters defined
by the user and a set of start templates defined for each target site/group of targets sites. Each tar-get
site/group of target sites is represented by a tree and the nodes of each tree represent the start
templates. A node is expanded by adding spacer templates to the partial skeleton, in accordance
with the initial constraints. The program proceeds by a series of tree pair connections until eventu-ally
a complete structure is generated.
Further details on ligand generation and docking can be found here
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Atom based interaction scoring
- Hydrogen bonds
- Van der Waals interactions
- Entropy
- Hydrophobic surface contact area
- Conformational strain energy
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Various criteria for sorting
- Gauche
- Stereo centres
- Counters
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Clustering Algorithms
- Ward
- Single link
- Centroid fingerprint counters
- 2D similarity
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