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

From the perspective of computational de novo screening, the ability to accurately predict the potential bound configurations of small low-molecular weight fragments to a target is essential. The challenge is significant given that the binding site may be large compared to the overall size of the fragment and the affinity of the fragments for particular regions of the binding site may be on the order of mM or less. Finally, it important to not only predict the poses with highest binding affinity (with small root mean square deviation to known structural biology solutions) but to predict a diverse ensemble of bound configurations of each fragment with a large distribution of binding free energies to the target. All of these requirements are crucial given that de novo/fragment design aims to obtain a robust nM affinity binding ligand by tethering weakly bound fragments derived mM to uM range.

The requirements for a fragment docking and scoring approach employed in a denovo design paradigm from our perspective are:
1) a procedure which provides exhaustive sampling of the potential bound fragment configurations in the binding site,
2) a sampling regime in which modest affinity fragment locations are sampled more effectively that low affinity sites,
3) for cases where structural biological solutions of the bound fragment configuration is known, one wants the pose prediction approach to have a good correlation of predicted docking score with docking poses with low RMS deviations from the structural biology solution.
A simple example is shown below that exemplifies these characteristics for the particular case of fragment docking of a fragment found in the pdb code 1OV7 where a small phenolic fragment (2-allyl-6-methyl phenol) is bound to T4 Phage Lysozyme.

Panel A in Figure 1 shows the overlap of the best scoring pose of the phenolic fragment with the crystal structure pose. The top scoring pose has an RMSD of 0.5 Å with respect to the crystallographic configuration. Panel B shows the correlation of the pose root mean square deviation with the eHiTS docking score. The plot illustrates that there is correlation of pose score with low RMSD particularly in the low RMSD/good score region. Panel C and D show the histograms of the RMS deviations and scores of the docked fragment poses. Note that the deviations peak in the good score/low RMSD regime, analogous to what is seen in the distribution in the RMSD vs. Score plot.

I’ll back in coming days to talk about fragment affinity scoring!

Posted by Dan Harris

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