SimBioSys Blog

The SimBioSys team is back from the ACS Meeting in Salt Lake City. It was a bit low on the attendance side, but was high on quality of some sessions like the FBDD, and the Adaptive Scoring Functions. There were lively discussions in drug discovery, and great events as usual, even with the smaller crowd.

Our Spring ACS 2009 presentations are posted at: http://www.simbiosys.ca/science/presentations/index.html
or you can also look at:
http://www.simbiosys.ca/science/presentations/2009-03-acs/index.html

We have also posted our poster presentation from the CHI’s Molecular Medicine Tri-Conference, (Feb 25-27 2009, San Francisco):
http://www.simbiosys.ca/science/presentations/2009-02-Tri-Conf/ SimBioSys_TriConference_Poster.pdf

You’re welcome to take a look.

by Aniko

We are less than one week away from catching our flights out west to the beautiful Salt Lake City and our time at another American Chemical Society meeting. We will of course do what vendors do and meet with our users, spend time in our booth #316, and have friendly exchanges with those other players in our domain. As readers of this blog will be aware that one of our primary areas of research is of course docking. It is no secret that SimBioSys operates in a highly competitive environment. Over the years many academic and commercial groups have done excellent work in innovating new methods in the world of docking. In parallel we have been delivering our own innovative contributions to this area, and this fact is strongly manifested in the high visibility of the company in the technical program of the 237th ACS meeting: a total of seven presentations will be delivered by SimBioSys scientists.

If you’ve been watching this blog you will have seen that we were the first to deliver a working docking solution on a Cell processor <http://www.simbiosys.ca/ blog/?s=cell> (either the PlayStation PS3 or on the IBM Cell Processor Blades). We also developed a novel scoring function, that works well with our exhaustive, fragment based eHiTS docking engine <http://www.simbiosys.ca/blog/2009/03/10/ fragment-pose-prediction-and-score-rmsd-correlations/>. We delivered the LASSO approach <http://www.simbiosys.ca/ehits_lasso/index.html> to examine 3D ligand activity surfaced-based similarity. We continue to do fundamental research (e.g. in scoring) to improve the scientific algorithms underlying our software. We are driven by delivering to our users the best algorithms, most appropriate workflows and simply the best tools for docking.

Driven by our science we are motivated to present our work at conferences such as the ACS meeting. With this in mind we submitted a number of talks to present. The list is below and includes our work on fragment based applications of eHiTS and SPROUT, the eHiTS speedup on the Cell platform and the new scoring function of eHiTS, as well as CAESA - the retro-synthetic scoring function. In addition SimBioSys will exhibit all of these software tools at Booth# 316. Our applications scientists Danni Harris, and our chief scientist & founder, Zsolt Zsoldos, and Peter Johnson, we will be delivering a total of seven presentations. That’s a lot of presentations even for a company 5 times our size. If you’re at the ACS please contact us to set up a one-on-one meeting with our scientists for scientific discussion and consultation. If you aren’t there we will post the presentations onto our website, here: http://www.simbiosys.ca/science/presentations/2009-03-acs/

1. COMP 1
   Session: Advancing Computational Chemistry through High-Performance Computing: From the Workstation to Petascale and Beyond: Michael Dewar Memorial Symposium
   Sunday, March 22, 2009 from 8:30 AM to 9:10 AM; SPCC — 257, Oral
   “Docking performance accelerated 30-50 fold on the Cell/BE processor”
   Presenter: Zsolt Zsoldos, See abstract

2. CINF 044
   SESSION: Library Design, Search Methods and Applications of Fragment-based Drug Design
   Tuesday, March 24, 2009 from 10:10 AM to 10:40 AM; SPCC — 254 A, Oral
   “Fragment based docking and linking engine of eHiTS”
   Presenter: Zsolt Zsoldos, See abstract

3. CINF 063
   SESSION: Adaptive Scoring Functions
   Wednesday, March 25, 2009 from 10:00 AM to 10:35 AM; SPCC — 254 A, Oral
   “eHiTS scoring function”
   Presenter: Zsolt Zsoldos, See abstract

4. COMP 208
   SESSION: Drug Discovery
   Thursday, March 26, 2009 from 8:30 AM to 9:00 AM; SPCC — 258, Oral
   “eHiTS: Docking and scoring ligand/target interactions to give good score-rmsd and ic50 correlations in in silico high throughput screening”
   Presenter: Danni Harris, See abstract

5. CINF 033
   “Computational tools for fragment based drug design”
   Monday, March 23, 2009 Salt Palace Convention Center — 254 A, Oral; 1:35 PM
   Presenter: A. Peter Johnson, See abstract

6. COMP 214
   Computational approaches to antibacterial and antimalarial hit finding”
   Thursday, March 26, 2009 Salt Palace Convention Center — 257, Oral, 1:00 PM
   . Presenter: A. Peter Johnson, See abstract

7. CINF 073
   “Scoring synthetic feasibility: A very different problem”
   Wednesday, March 25, Salt Palace Convention Center — 254 A, Oral, 4:05 PM
   Presenter: A. Peter Johnson, See abstract

One additional exciting presentation will be presented by Peter Johnson for our partner Elsevier. Prof. Johnson will be a guest speaker at the Elsevier’s ACS launch of Reaxys, a new Innovation from CrossFire Beilstein:

where: Special Events Pavilion, ACS exhibition hall,
when: Tues, Mar 24, between 2:00 pm and 3:30pm
title: “An introduction to Reaxys - the workflow solution for synthetic chemistry”

See more about this event at the Elsevier web-site: http://www.info.reaxys.com/event

David Bradley posted a great article today regarding “Drug Design on the Playstation”, read all about it here
http://www.reactivereports.com/chemistry-blog/drug-design-on-the-playstation.html

TORONTO, ON - 26th Feb 2009: SimBioSys Inc. announces the release of eHiTS 2009 - a new version of its molecular docking and virtual screening software. The new release builds on eHiTS’ strengths of its fine, systematic and exhaustive search algorithm, its automatic protonation state handling, and its unique knowledge-based scoring function. It delivers the following new features:

• An average 10x hardware-based speedup on IBM’s Cell/B.E. platforms.
• An improved scoring function up-to-date with the latest experimental data.
• Scoring function pre-tuned for 500 new protein classes.
• Dramatically improved correlation between score and binding affinity.

One of the greatest performance enhanced strategic advantages of this new release is the port of this accurate docking tool to the Cell platform. Molecular docking is often used as a virtual screening method for large libraries of compounds in an effort to identify potent molecules for pharmaceutical purposes. The substantial computational cost of this process has so far required computer clusters of considerable size, but the level of speedup achieved on the Cell processor allows replacing roughly 10 cluster nodes with a single PlayStation 3. “This is a low-cost and green hardware solution that saves on operational costs like cooling, electricity and space,” says Zsolt Zsoldos SimBioSys’ chief scientist, “it delivers the same high quality results as traditional platforms, and opens up the virtual screening paradigm to small companies who could not afford the IT infrastructure required for the process”.

In addition to the Cell-port, eHiTS’ scoring function has undergone a significant overhaul toward the release. “Our knowledge-based approach mandates keeping pace with the most recent publicly available experimental data”, says Zsoldos, “the new scoring function was trained on thousands of PDB structures as well as on activity and binding affinity data”. The current release offers score weight-sets that were tuned for 500 new protein classes. eHiTS attempts to classify the user’s targets in one of those families, and to use the appropriate scoring scheme which often provides better correlations of the score with low RMSD ligand-poses and with binding affinity. “These changes were shown to produce cutting-edge performance in enrichment studies, and state-of-the-art binding affinity prediction capability, which are essential to structure-based drug design,” Zsoldos adds.

SimBioSys is confident that this release positions the company at the forefront of the molecular docking field. “eHiTS 2009 provides a very powerful drug-discovery tool, and during the development of this version we have laid the foundations for additional improvements that will follow in the coming months”, summarizes Dr. Zsoldos, “In addition, the PlayStation solution directly delivers on two key issues in today’s dire market conditions: significant cost reduction with no compromise to quality, and lower environmental footprint due to lower power consumption.”

About SimBioSys:
Privately owned, SimBioSys is a recognized leader in the field of rational 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.

SimBioSys started its venture into retrosynthetic analysis almost by chance when researchers at Pfizer were looking into CAESA and enquired whether the approach for evaluating synthetic accessibility can be expanded and developed enough to provide full synthetic routes for target molecules. Thus began our journey along a path that has been explored by so many others with limited success so far. SimBioSys with its inherent computer science and computational chemistry expertise, joined forces with Peter Johnson at the University of Leeds - the mind behind CAESA and a well recognized organic chemist - to meet the formidable challenge. Fast forward to 2009, ARChem now offers arguably the most comprehensive solution to the great challenge of computer aided synthesis design.

Given the complexity of chemistry, one cannot but admire and be amazed at the capability of synthetic chemists to build increasingly complex molecules from simple building blocks. ARChem offers the chemists an idea-generating tool that can help them jump-start their synthesis design by proposing a manifold of synthetic routes that sometime utilize less obvious chemistry, and often lead to less frequently used starting materials. This is achieved by ARChem’s exhaustive approach to the retrosynthetic search, and, even more importantly, by its automatic mechanism for creating synthetic rules from rich and thorough databases of chemical reactions. The software’s unique way of handling the reaction rule generation process, which is the crux of this endeavour, has been discussed here and in scientific forums, such as the ACS national meeting. Now, the synthetic chemistry community, and the computational chemistry audience can explore the details of the approach and the algorithms in a new article published in the Journal of Chemical Information and Modelling:

SimBioSys scientific publications page or ACS - JCIM page

We are confident that this paper will not only draw attention to ARChem, but will also encourage further research and discussion about the role of computers in synthesis design in the years to come.

Researchers at an I.B.M. laboratory have captured a three-dimensional image of a a tobacco mosaic virus using magnetic resonance force microscopy with a spatial resolution down to four nanometers. The New York Times article reports: “Dr. Rugar and others were able to make an image of a single electron with the new technique. The new achievement is the dimensionality of the image. Magnetic resonance force microscopy employs an ultrasmall cantilever arm as a platform for specimens that are then moved in and out of proximity to a tiny magnet. At extremely low temperatures the researchers are able to measure the effect of a magnetic field on the protons in the hydrogen atoms found in the virus”. Since the technique does not require crystallization, it can be used to study structures hat have proven elusive for X-ray crystallography (e.g. membrane proteins). I hope it will give some high resolution 3D data to learn from and improve our models.

ZZ

Alex Wissner-Gross, a Harvard University physicist has wrote a study on the environmental impact of computing. The study got cited widely in main stream media, including the BBC and Times-Online as well. The study claims that a typical Google search generates about 7g of CO2, and the global IT industry generates as much greenhouse gas as the world’s airlines - about 2% of global CO2 emissions.

I have a serious fundamental problem with this study: it directs the blame in completely the wrong direction. Using computers or electricity for any purpose does NOT generate CO2 emissions! The sad fact that most of our electricity is currently generated by burning fossil fuels (e.g. coal) is the real problem not how we use the electricity or for what purpose. Unworkable cover-up ideas (clean coal) presented with publicity stunts don’t help either. There are working clean alternatives: solar, wind and hydro power plants, so electricity can be produced without CO2 emission, therefore the use of electricity and computers has ZERO carbon footprint. On the other hand, the world’s airlines burn fossil fuels directly, so comparing the IT industry to them for environmental impact is vastly unfair until the airlines switch over to use electric engines exclusively.

ZZ

We’ve been having the conversation within our company that the two dials of speed and accuracy work counter to each other. So, we’ve been espousing that even when it comes to the eHiTS Lightning solution that higher accuracy does take longer. We still stand by that BUT what we are happy about is the type of accuracy we can achieve very quickly using the new eHiTS Lightning algorithms. This becomes more obvious when our results are compared to the results of others. There has been a proliferation of arguments for GPUs being used as acceleration processors – we actually believe this is simply because of the business driver of “looking for new markets” for the GPU manufacturers. Zsolt has discussed his views regarding the future of High Performance Computing previously and commented on GPUs. Our belief is that while GPUs are clearly more “common” our decision to work with the Cell BE processor can certainly lead to far superior results…don’t forget that the RoadRunner computer is based on the Cell Processor, not GPUs. Did we make the right decision?

We are always watching for innovative solutions in docking. We acknowledge those scientists pushing towards the edge of performance and excellence. When we saw the recent announcement regarding the DockStar solution from Silicon Informatics we were interested to see whether they had made some of the promised breakthroughs with their GPU-based solution. Their website promises “With the combined power of the DockStar™ Linux Workstation, NVIDIA’s® Tesla™ GPU’s and our proprietary software kernels, Silicon Informatics’ DockStar™ solution outperforms conventional workstations by 10 - 20+ times.” The system is based on the Autodock 4.0 software platform. As commented in my recent blogpost we have been doing a lot of work to validate the performance of eHiTS Lightning and gathering validation data for throughput, pose accuracy and enrichment so we were interested to compare our data with those of the GPU-based DockStar solution. We’ll report the data in much more detail in a Case Study note presently in development but our observations at present are based on comparing to information they have on the site.

There are 3 examples posted on the home page of the DockStar site, 1stp, 3ptb and 1hvr, with the results shown below:

The table shows us that for these three examples at least we see a difference of over 10x in performance for the Cell processor versus the GPU-based Dockstar solution. Now, this is only a comparison based on speed. Accuracy is clearly just as important so how do we do there?

We are presently finishing the results for all examples but one example is shown below, in all its glory! Notice the dramatic performance difference in the plots below. The eHiTS Lightning shows the expected behavior in terms of the expected good, i.e. low scores at low RMSD values whereas DockStar/AutoDock accuracy / score correlation has no tendency. These results show that eHiTS Lightning not only offers dramatic speed advantages but also the accuracy advantages we have been espousing. More detail will be published soon.

	Img1: Autodock 4: 250,000 GA: 45 minutes, note the resultant RMSD distribution.
	Img2: eHiTS Lightning, on the CELL B/E. 1 minute, note the nature of the Scrore/RMSD distribution, most poses are at low RMSD values.