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Can we trust docking results?
Sept 2010

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Press Releases in 2010:



Independent user study ranks eHiTS at the top

TORONTO, ON - Sep 3rd 2010: SimBioSys, Inc. is pleased to inform the scientific community about the following recent paper in Wiley's Journal of Computational Chemistry:

"Can we trust docking results? Evaluation of seven commonly used programs on PDBbind database"

by Plewczynski et.al, from the University of Warsaw  (http://onlinelibrary.wiley.com/doi/10.1002/jcc.21643/abstract). They performed a comparison of 7 docking and scoring programs to evaluate pose prediction and score accuracy on a large set of 1300 PDB complexes. They performed a fairly thorough study asking some important questions, such as how the starting ligand conformations influence the results and how the results differ for small or large ligands, mostly hydrophobic or mostly polar interaction. The good news they report is that, statistically, overall results do not seem to be influenced by the starting conformations, although there is a slight advantage in some programs for the X-ray conformation, which is understandable. The bad news is that ligand size does matter: while we are very successful with small, fairly rigid molecules, large floppy ones still prove to be hard to handle for all programs. The really ugly news is that none of the scoring functions provided adequate correlation with binding energy.

The results are divided into 3 major sections: pose prediction accuracy, score correlation with experimental binding energy and score-rmsd correlation (ranking performance of the scoring functions). The authors' conclusion of the pose prediction exercise can be summarized by the following quote:

"On the basis of those results, we can order programs in the following way:  GOLD ~ eHiTS > Surflex > Glide > LigandFit > FlexX > AutoDock. The best programs have the average RMSD top score around 2.7 A, and it increases to nearly 4.5 A for the weakest FlexX. As expected, better results were observed for best pose conformations. For those poses, the mean RMSD value was even below 2 A for GOLD, eHiTS, and Surflex. ... Moreover, the percentage of pairs for which top score conformation is below 2 A shows that even for the best programs the success rate is below 60%, and in some cases even below 40%."

Based on the score-energy correlation performance, the authors divided the  programs into three categories. The best one is "composed of functions implemented in eHiTS and in Surflex, which gave Pearson correlation 0.38 and 0.33, respectively. Moreover, for eHiTS scoring function very high-Spearman correlation was obtained..." The Pearson correlations for the middle and worse categories are  in the range of 0.17-0.25 and less than 0.1 respectively. The authors rightly conclude that the score-energy correlation results are inadequate even for eHiTS.

Finally, in the ranking performance comparison (correlation of score with
quality of poses) AutoDock achieved the highest 0.32 correlation with eHiTS as close second with ~0.3 correlation.

So, what is the final conclusion of the authors with regards to answering the question in the title ? Here is the quote with the answer:

"Thus, can we trust docking programs? The answer must be given individually  for two aspects of docking programs. In terms of pose prediction, we can say that GOLD and eHiTS performance is accurate enough ... In the case of scoring functions, the answer must be negative, as virtually no correlations could be observed between docking score and in vitro binding affinities ... the empirically derived functions have now reached the saturation of year-to-year improvement ... The future direction should be either to use statistical approach based on increasing number of X-ray protein-ligand complexes, as can be determined from the results obtained by eHiTS scoring functions, or to develop completely new approaches in terms of predicting in vivo activity of the ligand."

Zsolt Zsoldos SimBioSys' chief scientist and main eHiTS developer says: "I am very happy to see that eHiTS came out at the top, i.e. among the best-2 contenders for all 3 aspects of the comparison while the other-best were three different programs for the 3 aspects. On the other hand, I agree with the authors that there is still a lot of room and need for significant improvements both in terms of pose prediction (~60% success rate) and score accuracy (~0.4 correlation). Furthermore, we definitely need such thorough and large-scale performance comparisons as this one in the future to continuously assess the state of the art until some programs (hopefully eHiTS remaining on the lead) will reach adequate performance."

About eHiTS: eHiTS is a flexible ligand docking and virtual screening software developed by SimBioSys, Inc.  By utilizing an exhaustive search algorithm, that rapidly enumerates mappings of interacting atoms between receptor and ligand the software employs new approaches to the classical problem of flexible ligand docking. The eHiTS software provides energy optimized 3D coordinates of docked poses and conformations of ligand molecules in the active site of the receptor. The binding energy of each pose is calculated and reported as a score. At the end of each run the ligand that produced the lowest binding energy (i.e. best score) is reported. The software is not only fast, but is also highly scalable, it's able to efficiently run from single desk-top PC's to multiCPU clusters, super-computers and  computer grids.

About SimBioSys: Privately owned, SimBioSys is a recognized leader in the field of cutting edge drug discovery software. Providing a wide range of software solutions, the company is focused on the development of scientific tools to facilitate the drug discovery process. It retains a constant focus on the innovation of algorithms to provide improved throughput and accuracy in the fields of flexible docking, virtual screening and de-novo structure design. SimBioSys is also a pioneer in the field of computer-aided retrosynthetic analysis where it supports chemists through the challenges of organic synthesis. With attention to detail, ease-of-use and improved productivity, SimBioSys has built a strong reputation of delivering state-of-the-art scientific solutions to biotechnology and pharmaceutical companies.


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