SimBioSys Blog

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

SimBioSys co-founders, Prof. Peter Johnson (UK) and Dr. Zsolt Zsoldos (Canada), along with our collaborator Dr. Sean Ekins (USA), delivered five talks at this past ACS meeting. They said that the meeting was a great opportunity to catch up with people they know and to meet new people. According to them, many of the other talks they attended were inspiring, and now, as they are making their journeys back home, their presentations are being posted here to share the science with you:

http://www.simbiosys.com/science/presentations/index.html

Peter Johnson et.al.: “Automated retrosynthetic analysis: An old flame rekindled”
view slides
http://www.simbiosys.com/science/presentations/2010-08-acs/ARChem_ACS_Boston_2010_final.pdf
Sean Ekins et.al.: “LASSO-ing potential pregnane X receptor agonists”
view slide
http://www.simbiosys.com/science/presentations/2010-08-acs/ACS2010_LASSO.pdf
Zsolt Zsoldos et.al: “How eHiTS solves the docking and scoring problems”
view slides
http://www.simbiosys.com/science/presentations/2010-08-acs/ACS2010_eHiTS_lessons.pdf
Zsolt Zsoldos et.al: “Scoring performance of eHiTS on the CSAR dataset”
view slides
http://www.simbiosys.com/science/presentations/2010-08-acs/ACS2010_CSAR_ehits_score.pdf
Zsolt Zsoldos et.al: “Protein-ligand docking on the Cell/BE processor with eHiTS Lightning”
view slides
http://www.simbiosys.com/science/presentations/2010-08-acs/ACS2010_HPC_ehits.pdf

posted by: Aniko

Only 10 days left to the upcoming ACS meeting in Boston (Sun Aug 21 - Thurs Aug 26), and most of the people attending are preparing their personal schedules: the must-go-lectures, the booths at the expo floor showing the latest and greatest technology, and the social networking and get-togethers.

SimBioSys will be there with no exception. We will be showcasing our latest product releases at booth: # 945. The focus will be on the new:
* ARChem 2010 release:
http://www.simbiosys.com/blog/2010/07/06/a-new-archem-release-integrable-more-efficient-and-better-performing/
* The upcoming CLiDE v 4.0 release that is currently in BETA testing - and shows significant improvement in recognition of chemical structures from PDF files and images.
* eHiTS, the exciting participant of the first CSAR benchmark exercise!

The science, algorithms and software design that are embodied in these products will be discussed in five different talks given by:

Zsolt Zsoldos:

COMP 25:
How eHiTS solves the docking and scoring problems
Session:Drug Discovery (08:30 AM - 11:45 AM)
Time: Sunday, August 22, 2010 09:30 AM
Location: Boston Convention & Exhibition Center
Room:Room 154

COMP 59
Protein-ligand docking on the Cell/BE processor with eHiTS Lightning
Session: Scripting & Programming
Time: Sunday, August 22, 2010 03:50 PM
Location: Boston Convention & Exhibition Center
Room: Room 157A

COMP 122
Scoring performance of eHiTS on the CSAR dataset
Session: The Community Structure-Activity Resource (CSAR) Scoring Challenge (09:00 AM - 11:50 AM)
Time: Monday, August 23, 2010 10:05 AM
Location: Boston Convention & Exhibition Center
Room: Room 157B

Peter Johnson:
CINF 42
Automated retrosynthetic analysis: An old flame rekindled
Session: The Journal of Chemical Information and Modeling’s 50th Anniversary Symposium
Time: Monday, August 23, 2010 - 11:40 AM
Location: Boston Convention & Exhibition Center
Room: Room 156A

Sean Ekins who has been collaborating with us in the past few months:
TOXI 4
LASSO-ing potential pregnane X receptor agonists
Session: General Papers
Time: Sunday, August 22, 2010 09:00 AM
Location:Boston Convention & Exhibition Center
Room: Room 252B

We hope you will find these talks interesting and that you will catch up with the SimBioSys researchers either following these presentations or at the booth. If you would like to schedule a meeting with us in advance please contact: aniko *at* simbiosys dot com

Have a great ACS meeting, and an enjoyable trip to Boston.
posted by Aniko

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

We are dedicated readers of Derek Lowe’s wonderful blog about the  pharmaceutical industry and drug discovery. With his witty style, Lowe is covering many aspects of this field, and is shedding light on many facets that are not always very obvious for people like us who are not directly involved in drug discovery. It is no surprise that the blog has attracted a  sizable group of commentators that add their own experienced perspectives to the posts.

One of his latest entries discussed the concept of the “Ideal Synthesis”.  While largely an elusive notion, thinking about what constitutes a good synthesis, is an important discussion that we constantly hold between us and ARChem’s users. After all, typically ARChem generates a whole range of synthetic routes to target molecules, and while the user can browse through them all and choose the more useful routes in the specific scenario, the system does offer its own prioritization of solutions as a means of assistance to the user. The rank ordering of synthetic routes is trying to mimic a chemist’s  perspective, but this in itself, is not a well defined entity. Although we know what are the essential components, like: yield, minimal wastage, few synthetic steps, and robust reactions, striking the (or a) right balance between the terms is tricky. Lowe’s blog post, the paper it refers to, and the ensuing discussion there, are very helpful.

links:
http://pipeline.corante.com/archives/2010/06/29/the_ideal_synthesis.php
http://pubs.acs.org/doi/abs/10.1021/jo1006812

posted by Aniko

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

The Fields Institute, located in Toronto, is a center for mathematical research activity - a place where mathematicians from Canada and abroad, from business, industry and financial institutions, come together to carry out research and formulate problems of mutual interest.

SimBioSys founder and CSO, Zsolt Zsoldos, who is both a mathematician / computer scientist and a chemist, was recently invited to speak at one of the Fields’ Seminars. This was a great honour and recognition of the scientific
work he does at SimBioSys with his team of exceptional and talented researchers. The title of the March 2nd, 2010 presentation was: “Algorithmic and mathematical challenges in protein-ligand docking and scoring”, which has been a significant part of Zsolt’s work in the past 10 years. He tried squeezing it into just a 1 hour session, and that alone was a huge challenge. Nevertheless, there were many sparkling eyes in the audience, and hopefully the whole topic created enough interest so that we’ll see a few more mathematicians in this challenging field of science in the future. You can check out Zsolt’s talk at: http://www.simbiosys.com/science/presentations/index.html#2010
the audio and slides of the talk will be also shortly posted at Fields Institute’s web site at: http://www.fields.utoronto.ca/audio/#optimization_seminar

Another current, and interesting talk by a SimBioSys’ scientist will be given by Orr Ravitz at the upcoming spring 2010 ACS meeting in San Francisco. He will be talking about “Improving molecular docking through eHiTS’ tunable
scoring function”, in the Drug Discovery session on Monday March 22, 2010 at 10:00 am.

Abstract: The molecular docking paradigm has been hampered by the lack of a generically well performing scoring function. We present two complementary family-based approaches for score-tuning that improve docking performance  using experimental data. One technique treats the relative weights of the eHiTS energy terms as parameters that can be adjusted to improve score-RMSD correlations. The other technique is employing ligand-based similarity to rescale the docking score such that better enrichment factors are achieved in virtual screening. We discuss the algorithmic details of the methods, and demonstrate the effects of score tuning on a variety of targets, including CDK2, BACE1 and AChBP, as well as on common benchmarks. We observe an average improvement of 10% in the top-rank pose RMSD, and a similar improvement for docking success (top pose under 2 A). An average EF(1%) of 15 is achieved for the targets in the DUD set.
http://abstracts.acs.org/chem/239nm/program/view.php?obj_id=9832&terms=

Should be a discussion starter! Please join us for the session if you’ll be at the ACS meeting in SFO in two weeks, and contact us if you would like to meet  with us during the days of the conference.
posted by Aniko