SimBioSys Blog

One of our customers recently asked us to provide him with a short presentation explaining our retrosynthetic analysis software, ARChem, so that he would be able to advertise it to potential users within his organization. Since, to paraphrase the old adage, a clip is worth a thousand slides, we opted for a 5 minutes video.

It’s not easy to squeeze the essence of a product like ARChem into a short video, since it has so many facets: the search engine, the solutions display, solutions filtering, interfacing with reaction databases not to mention all the science that is at work under the hood. So we decided to focus on the core value of ARChem: the ability to harvest knowledge from experimental data, and to convert the knowledge to ideas. In 5 minutes we show, without discussing the fascinating underlying technology, the available search strategies, solutions viewing and construction, sharing ideas with your fellow researchers, and viewing literature examples. Please see the movie at:

http://www.simbiosys.com/archem/video/

We hope you will find it interesting.

Whether you are at work, at home or on a trip this summer, you can stay informed about the latest software tools of SimBioSys. Three of our products: CLiDE, eHiTS and ARChem, will be showcased in rotation on our weekly seminar series. Join us for these one hour online sessions given every Thursday at noon, EDT.

Starting July 14th we presented CLiDE (Chemical Literature Data Extraction) office tool - which can extract chemical structures embedded in PDF files, Word documents, JPEG and TIFF files, and other document and picture formats. CLiDE is a productivity and convenience tool, it saves the time and trouble of copying useful, and often complex structures from an image into a chemical editor or an e-lab notebook. It is useful for your everyday work, as well as for creating chemical knowledge-bases from journal articles, patents, and web content. (http://pubs.acs.org/doi/abs/10.1021/ci800449t)

There will be two more sessions for CLiDE:
* Thurs., Aug 4, 12 noon EDT
* Thurs., Aug 25., 12 noon EDT

On July 21st we presented eHiTS and its utilities (LASSO, CheVi, Score and Tune) for molecular docking and virtual screening. With its exhaustive conformational search, automated protonation state handling mechanism, and a tunable scoring function eHiTS provides one of the top-performing algorithms in the field: “the fastest” [1], “the most accurate” [2], and “the easiest to use with automated protonation/tatutomerization assigments” [3].

There will be two more sessions for eHiTS
* Thurs., Aug 11, 12 noon EDT
* Thurs., Sep 1., 12 noon EDT

On July 28th we presented ARChem, the newest tool to help organic chemist with synthesis planning.  Synthetic chemists in industry nowadays face an enormous challenge: to develop novel  chemicals, faster, safer, greener and cheaper. In order to solve this multi-dimensional problem most chemists make some use of reaction databases but these are most helpful when the synthesis of the target entity has already appeared in the literature.

ARChem Route Designer is a tool which goes well beyond this and is a computer system designed to support the organic synthetic chemist in the planning the synthesis of novel as well as known compounds. Its features include:

* reaction rules generated by automated mining of large reaction databases
* application of those rules on-the-fly in a retrosynthetic fashion to convert a novel chemical target all the way to readily available starting materials
* display of information from multiple resources (such as literature reactions from Reaxys (*), and starting materials from multiple vendors) in the system
* scoring the many alternatives based on various criteria (shortest path, highest yield, lowest material cost and other options)

There will be two more sessions for ARChem
* Thurs., Aug 18, 12 noon EDT
* Thurs., Sep 8., 12 noon EDT

The webinar sessions are live, and they provide you an opportunity to ask questions and receive  immediate feedback. In case you missed the session you can always view its recording, or join us during the next session on the product of your interest.

Don’t miss out this opportunity, register now at:
http://www.simbiosys.com/products/webinar_request.html
We are looking forward to seeing you at our summer webinars!

posted by: Aniko

References:
[1]: Quote from Dr. Katie Simmons, University of Leeds, UK
[2]: http://onlinelibrary.wiley.com/doi/10.1002/jcc.21643/abstract
[3]: Quote from Dr. Mihaly Mezei, Mount Sinai School of Medicine, NY, USA

Notes:

(*) Reaxys and Reaxys Data represented in ARChem Webinar is used with kind permission of the copyright owner Elsevier Properties SA.
Copyright 2010-2011 (c), Elsevier Properties SA, All rights reserved. Authorized use only.  Reaxys(r) is a trademark owned and  protected by Elsevier Properties SA and used under license.

We gave two presentations this week at the Spring 2011 ACS meeting in Anaheim,  Calif. One was about eHiTS, in the session: “Docking and Scoring: A Review of Docking Programs”, and the other was about ARChem, in the computer aided synthesis design symposium in honour of Prof. J.B Hendrickson. Both presentations are now available online for anyone to review and comment. Feel free to post your comments here on this blog post or provide feedback offline.

Orr Ravitz presented on overview of the CASD field with lessons learnt from the past and suggested ways forward. Presentation title: “Back to the future of synthesis planning: how new technology and new resources revitalize the vision of computer aided synthesis design”;
view presentation. ( http://www.simbiosys.com/science/presentations/2011-03-acs/ARChem_241_ACS_web.pdf )

Zsolt Zsoldos presented eHiTS 2009.1 results on the cleaned up Astex-set  (goal assessment of docking pose prediction accuracy) and DUD-set (goal assessment of virtual screening power of docking). The data was curated and mandated by the symposium organisers by Dr. Greg Warren and Dr. Neysa Nevins. Lessons learnt: with clean / better data, one gets better docking accuracy! See the latest eHiTS results with this data set, in our presentation: “Recent developments in the eHiTS ligand docking and scoring software“;
view presentation. ( http://www.simbiosys.com/science/presentations/2011-03-acs/ACS2011_eHiTS.pdf )

posted by: Aniko

By now most of you are back from the holidays and the off-work relaxation. Hopefully re-energized, ready to tackle new challenges and to pursue new opportunities. At least we feel so at SimBioSys. Hence we have just released the great new ARChem 2011!

This major release includes all the concepts covered by the recent beta version, plus more:

- Better chemistry: refinements in the treatment of halogens and carbonyl groups to present more accurate chemistry.

- New solution viewing concept: the user is in control of selecting the best solution(s). The display is a hybrid between step-by-step solution construction and full synthetic route presentation, and solutions browsing is dramatically faster and more accessible.

- User can add or edit the price of any starting material or intermediate, and modify the yield of any step in the solution tree.

- The PDF export utility has been revised, and full solutions, including starting materials details, can be presented in a concise document.

- Additional updates include:
* The Marvin editor inside ARChem, as a result we now support Mac and Windows 64-bit platforms.
* Starting material catalogues, including Acros and AlfaAesar’s latest 2010 listings, and the eMolecules catalogue.
* ChemInform reaction database with latest 2010 version, introducing 80,000 new reactions.

For more details, please see the “Version info” link under the Miscellaneous menu item in the new system.

All the existing user accounts have been migrated to the new address:
https://archemdemo.simbiosys.com/ARChem
Thus you can login using your old account, if you forgot your username and password, you can reset it using the “Forgot your username/password?” link,  and if you do not have an account, you can submit a request for one at: http://www.simbiosys.com/products/demo_request.html

Many of the new features and improvements are the result of feedback that we get from users. This is the best way for us as developers to navigate our work toward a product that genuinely addresses your needs. Please send us your comments, big or small, on any aspect of your experience with ARChem. We are looking forward to your suggestions (via the feedback or bug report link in the system, or simply directly to us via email) as to what you would like to see improved in ARChem in 2011.

We appreciate your business and support for SimBioSys, and we look forward to working with you this year again.

HAPPY NEW YEAR!
from all of us at SimBioSys, Inc.

CLiDE is a sophisticated chemical OCR application, that can extract molecular structures from images or PDF files, and can save them in several chemical file formats like: MOL, SDF and XML, or transfer them seamlessly to various chemical editors.  CLiDE is available in three packages: Standard, Professional or Batch. Each of them is serving a slightly different need at different prices.  CLiDE-Standard and CLiDE-Professional offer a contemporary graphical user interface, with all the recognition features embedded in a user-friendly document/image viewer,  for more info see: http://www.simbiosys.com/products/leaflets/CLiDE_folder.pdf

Release 4 contained major improvements to the product including:

• improved recognition accuracy
• improved input & output file format handling: introduced support for several new raster image file formats (GIF, JPEG, PBM, PGM, PNG, PNM, PPM, XBM, XPM); and introduced XML output file format that can be loaded for later editing
• introduced capability to extract chemical structures from tables
• saving molecules with super atoms in expanded or contracted form

Complete listing of changes is available upon request.

Feel free to contact me if you have any questions about this new CLiDE release, or sign up for a no-fee evaluation of CLiDE on our website: http://www.simbiosys.com/products/demo_request.html

posted by Aniko

The question is asked and answered by a group of researchers from the University of Warsaw in a recently published paper (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.

“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 (Fig. 4). 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 the best program, namely, 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.”

I am very happy to see that eHiTS came up among the best-2 contenders for all three 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.

…
Posted by Zsolt

One of the aspects of maturation is the transition from the egocentric viewpoint to a phase where one engages and considers others. It is true for kids that begin to understand and cope with social situations. It is true for soccer players, or scientists for that matter, that understand that it is not all about personal skills and knowledge, but it is also about how you utilize those in the team play. And it is true for software applications that shift from the stage of proving their algorithms’ capabilities, to become integrable with other applications and merge into a workflow that creates real value for the user.

Since the previous release, work has continued on improving reaction rules generation in ARChem as well as the retrosynthetic search. Significant progress has been made in detecting and highlighting potential functional groups interference. The chemoselectivity issue is a challenge that requires a combination of data mining, profound chemical perception, and supplemental expert knowledge-bases. Another area that recorded a significant improvement is scoring. The retrosynthetic search commonly generates a vast solutions-space with hundreds, and possibly thousands of paths. Navigating systematically through all the options is typically too time consuming, and scoring becomes pivotal in prioritizing the solutions for the user to inspect. Scoring now better reflects a chemist’s assessment regarding the feasibility of a synthetic route. It accounts for synthetic depth, reliability of individual reaction steps, yield, wastage, chemical interference and other considerations in a successful balance.

Alongside the major improvements in the underlying technology, the focus of the last few months has been on usability and integrability:

1. Reaction examples are directly linked to the Reaxys records for full data and literature access.

2. Starting materials arrived at during the search are pointing to the corresponding records in online chemical vendors catalogues.

3. Costs of starting materials are displayed, and route cost is evaluated.

4. As a rule is being used in the analysis, the example reactions that were used to generate this rule are now ordered by relevance to the synthetic route.

5. The solutions space can be pruned using user-defined filters.

6. Changes to the GUI make solutions navigation more efficient, and the general look and feel of the system is more polished and refined.

Here is an example that demonstrates some of the features mentioned above, and also elegantly validates the concept of automated retrosynthetic chemistry. The suggested route was ranked number 1 by the system. It manifests a sequence of three reaction rules that simplify the target all the way to commercially available starting materials,  shown with their associated prices per mole. In this particular  case, all the suggested transforms were actually exactly found in the set of reactions that generated the respective rules during the automated process of retrosynthetic-rule extraction. All the examples, and the exact-matches can be accessed via the links provided along the retrosynthetic tree. At the bottom right we show a literature reference for a synthesis of the molecule validating the route.  ARChem offers a set of 28 distinct solutions that constitute a gateway to a much larger solutions space that can be accessed through the “n of m transforms” links. The user can build different solutions by selecting any of the suggested alternative transforms.

ARChem has made a long way from its proof of concept days. It is now maturing into a tool that can offer real benefits to the medicinal or process chemist, not the least thanks to the continuous feedback that we get from users. In the next few months substantial changes are anticipated in all the aspects of the system. Maturity does not mean stagnation – ARChem is at the forefront of the field of computer aided synthesis design, and intensive R&D guarantees that major advances are still to come. Stay tuned.

posted by Orr

There was an interesting article published recently in the Biophysical Journal, (Volume 98, Issue 5, 872-880, 3 March  2010, doi:10.1016/j.bpj.2009.11.016), in which biophysicists recognise the importance of protonation state induced changes upon binding - and mention that one of its key practical applications is in structure-based drug design.

Dr. Alexey Onufriev from Virginia Tech and his team investigated three types  (small molecule, protein and nucleic acid) of ligands and their ionization state changes upon protein-ligand binding. They concluded that in all tree cases substantial changes can be observed both in the ligand and also in the receptor ionization states upon binding.

This is a very important observation for virtual screening and docking, because this proves our belief that protonation states of the proteins and ligands can not and should not be prepared and / or fixed for virtual screening experiments. Therefore eHiTS’ method of assigning the protonation  states on-the-fly is probably the best method to-date offered to solve this problem. For more info on eHiTS’ automated protonation state handling, please see our technical note with the same title on this page: http://www.simbiosys.com/ehits/ehits_technical_notes.html

posted by Aniko