As posted by Noel and Rich was the Java-based AstexViewer just got LGPLed and voila! Here it is, the OpenAstexViewer for structure-based drug design.
I personally was especially interested in the electron density functionality and how easy it would be creating a view on an enzymatically active-site.
As example I used Lisinopril an ACE (Angiotensin-converting enzyme) inhibitor. This class is seen as one of the success stories of rational drug design, based on the structural biology of carboxypeptidase A and medicinal chemistry.
My first thought was using Captopril, the initial drug for this class, but I could not find an electron density map and had to pick another example. Since the PDB structure (2C6N) of Lisinopril has a deposited electron density map this was now used.
After downloading the program and loading the structure and the map, I needed only a few mouse-clicks for selecting the ligand and creating a view on active site surface. Here is the result.
The drug is shown in the active site as sticks using atom coloring with having the zinc ion on the left in gray. The active site surface shows the lipophilicity of the protein residues. In orange we see the electron density map, which indicates a reasonable binding mode of this ligand.
Finally, but a little off-topic, I was also curious, if LASSO on ChemSpider identifies this molecule as an ACE inhibitor? In short, yes this target class gets one of the highest scores. Nice, having some online tools around for collecting quickly drug information.
After all of this I must say that the OpenAstexViewer is a very elegant, easy to use tool, which is extremely powerful. Has anyone tried already the scripting abilities ?
References
- M. Adam, Integrating research and development: the emergence of rational drug design in the pharmaceutical industry, Stud Hist Philos Biol Biomed Sci, 2005, 36, 513-37. PDF.
PMID: 16137601 - H.R. Corradi, S.L. Schwager, A.T. Nchinda, E.D. Sturrock, K.R. Acharya, Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design, J Mol Biol, 2006, 357, 964-974. PMID: 16476442
Posts
5 comments:
Joerg, Nice to see your comment about LASSO. A technical note is in development right now that I believe will be quite impressive regarding the applications of LASSO to the identification of estrogen binders using ChemSpider.
I am glad to see you are using the LASSO results on ChemSpider and I am even happier that the activity estimate was correct. In general, LASSO is really meant to be a pre-filter in virtual screening, its task is to eliminate structures that do not have any chance of binding to the target. The remaining candidates should be fruther evaluated by an accurate docking tool, like eHiTS:
http://www.simbiosys.ca/ehits/
Zsolt Zsoldos (akak ZZ)
Zsolt, actually I am not too surprised that the ACE inhibitor was found, since I guess this one might have been part of the training set, was it?
Can you comment on this and the performance on molecules not being part of the training set?
Furthermore, are there any validation and performance comparisons of eHITS against other docking tools published, e.g. against GLIDE or MOE?
Joerg,
The training set we used for LASSO is also up on ChemSpider, for ACE it is at:
http://www.chemspider.com/docs/lasso/ACE.pdf
Seems like your test case does not match any of them exactly, but there are some similar ligands in the set. We have published test results for 40 families (the DUD set) recently, test sets are all disjunct from training sets:
JCAMD, vol 22, Num 6-7, June/July 2008, pp 479-487, doi: 10.1007/s10822-007-9164-5
We have included some docking result comparisons with other tools in our eHiTS papers:
J.MGM Vol 26, 1, July 2007, pp 198-212; doi:10.1016/j.jmgm.2006.06.002
Current Protein and Peptide Science, 2006, vol 7, pages: 421-435, Number 5, October 2006.
Unfortunately, we were not included in third party published evaluations, but asked some authors to perform the same tests with eHiTS after publications, e.g. Merck's comparative enrichment study by Wendy Cornell's group was repeated with eHiTS, you can see the results here:
http://www.simbiosys.ca/ehits/ehits_enrichment.html
Similarly, a published comparative validation study was repeated with the same data by one of our academic users Dr. Fedor Zhuravlev from Denmark:
http://www.simbiosys.ca/ehits/ehits_validation.html
There is also a list of publications by various users of eHiTS here:
http://www.simbiosys.ca/science/user_pubs/index.html
Zsolt
Zsolt, thanks for the detailed update. It will take me a while digging through it ...
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