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IBM's Systems & Technology Group releases a white paper with
eHiTS & Cell
Oct 2008 Can we trust docking results? Evaluation of seven commonly used programs on PDBbind database
Sept 2010
EPA's ToxCastTM project will use SimBioSys' eHiTS as docking engine
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[Events]
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| 240th ACS
Aug 22-26, 2010
Boston, MA, USA
booth #945
see >> more
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Title: The eHiTS scoring function
Zsolt Zsoldos,
Danni L. Harris
SimBioSys, Inc., 135 Queen's Plate Dr., Unit 520, Toronto, ON, M9W 6V1,
Canada
Abstract:
The fragment-based exhaustive flexible
ligand docking engine of eHiTS has been published previously [1].
Recently, our efforts were focused on developing an innovative scoring
function for eHiTS, one which departs from the traditional atom-based
interaction scoring that is typical to most empirical, force-field
based and statistical scoring methods. We have introduced a novel
concept of scoring interactions based on Interacting Surface Points
(ISP) that are represented by their 3D positions, normal vectors and 23
chemical feature types including H-bond donor/acceptor,
aromatic Pi electrons, hydrophobic groups. A statistically derived
empirical scoring function is constructed using a 4-parameter geometric
description of the relationship between ISP pairs. The parameters
include the distance between the pairs of ISPs, the angles between the
normal vectors. The energy associated with each possible ISP pair is
deduced from statistics based on an inverse application of the
Boltzmann distribution function. During the statistics collection
temperature factors were considered with the corresponding Gaussian
functions applied to the atom positions to account for the variable
uncertainty of the atom positions in the Protein Data Bank (PDB) X-ray
structures. More accurate geometric statistics have been collected from
the Cambridge Structure Database and recently incorporated into the PDB
data. Certain atoms, for example, the nitrogen atom in the imidazole
ring, may participate in very different types of interactions at the
same time (H-bonding and aromatic Pi-stacking). The ISP representation
can describe these interactions better than the atom-based approach by
having multiple ISPs associated with the same atom but pointing in
different directions.
The advantage of the statistically driven ISP scoring function is
demonstrated on a case study using the Acetylcholine Binding Protein
(AChBP) which has a key cation-Pi interaction observed
crystallographically for several substrates (e.g. CCE, Nicotine,
Lobeline, Epibatidine) [2]. Empirical and force-field based scoring
functions fail to rank the correct binding pose highest even when using
DFT-6-31**B3LYP charges. In contrast, eHiTS produces the correct pose
with the best score even when using the default statistical table and
weighting scheme for which no example from this protein family was
included. When the automated training script is run to include the
family in the knowledge base then the energy separation between the
correct pose and other generated poses improves and provides very
cleanly distinguished clusters. Furthermore, the eHiTS score gives a
good correlation with the experimentally measured log(Kd) values for
the series, correctly rank ordering the actives.
eHiTS flexible docking has proved to be among the most accurate pose
prediction tools [4] and combined with the LASSO [3] ligand based
filter it provides one of the highest enrichment factors based on
comparative evaluation studies [5]. While LASSO can rapidly and
efficiently reduce the number of candidates to be docked to a few
percent of the total database, accurate flexible docking with eHiTS
used to take several minutes of CPU time per ligand on traditional
hardware architectures. The algorithm has been recently redesigned and
coded to take advantage of the Cell B/E accelerator architecture
providing between 30-100 fold speed-up [6] and bringing the runtime down
to a few seconds per ligand on a Sony Playstation PS3 gaming machine or
even faster on an IBM Cell Blade while still producing the most
accurate flexible docking.
The revolutionary hardware technology requires new computational
methods, replacing approximate pre-computed grids with proximity
look-up and explicit pair-wise interaction computation. As a result,
the calculation is not only orders of magnitude faster, but it also
provides more accurate energy predictions. The emerging technologies
presented could also be applied to speed up other molecular modeling
related problems, e.g. QM or MD simulations and protein folding, by
multiple orders of magnitude.
References:
[1] Z. Zsoldos, D. Reid, A. Simon, S.B. Sadjad, A.P. Johnson: eHiTS a
new fast, exhaustive flexible ligand docking system;
J.Mol.Graph.Modeling. (26), 1, 2007, 198-212;
doi:10.1016/j.jmgm.2006.06.002
[2] S.B. Hansen, G. Sulzenbacher, T. Huxfold, P. Marchot, P. Taylor, Y.
Bourne: Structures of Aplysia AChBP complexes with nicotinic agonists
and antagonists reveal distinctive binding interfaces and
conformations. The EMBO Journal (2005)24, 3635-3646.
doi:10.1038/sj.emboj.7600828
[3] D. Reid, B.S. Sadjad, Z. Zsoldos, A. Simon: LASSO - ligand activity
by surface similarity order: a new tool for ligand based virtual
screening.
Journal of Computer-Aided Molecular Design,
http://dx.doi.org/10.1007/s10822-007-9164-5,
doi: 10.1007/s10822-007-9164-5
[4] M. Kontoyianni, L.M. McClellan, G.S. Sokol: Evaluation of Docking
Performance: Comparative Data on Docking Algorithms,
J.Med.Chem., 2004; 47(3); 558-565.
eHiTS results for the same test case added by Fedor Zhuravlev,
Assist.Prof., Technical
University of Denmark:
http://www.simbiosys.com/ehits/ehits_validation.html
[5] G.B. McGaughey, R.P. Sheridan, C.I. Bayly, C. Culberson, C.
Kreatsoulas, S.
Lindsley, V. Maiorov, J. Truchon, W.D. Cornell: Comparison of
Topological, Shape, and Docking Methods in Virtual Screening.
J.Chem.Inf.Model. 2007; 47(4), 1504-19. DOI: 10.1021/ci700052x
eHiTS results added by Merck:
http://www.simbiosys.com/ehits/ehits_enrichment.html
[6]
http://www.bio-itworld.com/inside-it/2008/05/gta4-and-life-sciences.html
See full presentation
For
more information see the product's web page: http://www.simbiosys.com/ehits/
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