So much to do, so little time

Trying to squeeze sense out of chemical data

Archive for the ‘cheminformatics’ Category

New Versions of rcdk & rcdklibs

without comments

With the recent stable release of the CDK (1.3.12) and the inclusion of the new rendering classes, I was able to make a new release of the rcdk (3.1.1) and rcdklibs (1.3.11) packages that support cheminformatics in R. They’ve been pushed to CRAN and should be visible in a day or two. The new features in the latest version of rcdk include

  • Directly evaluate molecular volume (based on group contributions) using get.volume
  • Generate fingerprints using the hybridization state
  • and work sensibly
  • Added a function ( that copies the 2D depiction of a molecule to the system clipboard in PNG format
  • Now, OS X users can view and copy molecule depictions. This is slower compared to the same operation on Windows or Linux since it involves shell’ing out via system. But it is better than not being able to view anything.

Written by Rajarshi Guha

June 18th, 2011 at 7:41 pm

Posted in cheminformatics,software

Tagged with ,

The CDK Volume Descriptor

with one comment

Sometime back Egon implemented a simple group contribution based volume calculator and it made its way into the stable branch (1.4.x) today. As a result I put out a new version of the CDKDescUI which includes a descriptor that wraps the new volume calculator as well as the hybridization fingerprinter that Egon also implemented recently. The volume descriptor (based on the VABCVolume class) is one that has been missing for the some time (though the NumericalSurface class did return a volume, but it’s slow). This class is reasonably fast (10,000 molecules processed in 32 sec) and correlates well with the 2D and pseudo-3D volume descriptors from MOE (2008.10) as shown below. As expected the correlation is better with the 2D version of the descriptor (which is similar in nature to the lookup method used in the CDK version). The X-axis represents the CDK descriptor values.

Written by Rajarshi Guha

June 17th, 2011 at 11:42 pm

Posted in cheminformatics,software

Tagged with , , ,

New Version of fingerprint

with 3 comments

I’ve submitted version 3.4.3 of the fingerprint package to CRAN, so it should be available in a day or two. It’s an R package that lets you read in (chemical structure) fingerprint data from a variety of sources (CDK, MOE, BCI etc) and perform a variety of operations (bitwise, similarity, etc.) and visualizations on them.

The two main additions to this version are

  • Read support for the new FPS fingerprint format described by Andrew Dalke at the chemfp project. Note, it currently discards some of header information
  • The fingerprint class now has a field, misc, (a list) that allows one to read in extra, arbitrary data that might be provided along with a fingerprint. Exactly what gets stored in this field depends on the line function used to read in the fingerprint data. Currently only the FPS parser returns extra data (when available) in this field.

As always, you can get the package source directly from the Github repository.

Written by Rajarshi Guha

June 3rd, 2011 at 12:13 am

Posted in cheminformatics

Tagged with , ,

MIOSS Workshop Wrap Up

without comments

The last few days I’ve been at the EBI, attending the Molecular Informatics Open Source Software (MIOSS) workshop. As part of this trip to the UK, I’ve also had the opportunity to present some of the work my colleagues and I have done at the NCTT – thanks to Mark Forster for the invitation to speak at Syngenta and to John Chambers for having me speak to the ChEMBL group. At the workshop I presented my work on cheminformatics in R.

The focus of the workshop was to bring OSS developers and users from industry and academica/government together to hear about a variety of projects and discuss issues underlying the development and use of these projects. There were some very nice presentations – I won’t go into too much detail but some highlights for me included

  • Kevin Lawson (Syngenta) presented his work on LICSS – integrating the CDK with Excel. While I’ not a fan of Excel, it’s a necessary evil. I was quite surprised at the performance he acheived for substructure searches within Excel and the ability to access various functionalities of the CDK as Excel functions. While it probably won’t replace Accord or ChemOffice right now, it’s something to take a look at.
  • Mike Bodkin (Lilly) spoke about the use of KNIME at Lilly. They have built up an extensive collection of commercial and OSS nodes and it’s clear that KNIME is capable of giving Pipeline Pilot a run for its money. Thorsten Mienl then spoke of the OSS development of KNIME, and mentioned that they now support a collection of HCS and image analysis nodes (courtesy MPI Dresden). This is quite interesting, given that we’re ramping up our HCS capabilities at the NCTT
  • Hans de Winter of Silicos spoke about the tools and services that their company has produced on top of OpenBabel (and contributed back to the community). Quite encouraging to see a cheminformatics company making money of the OSS stack
  • Greg Landrum spoke about RDKit, presenting the RDKit based catridge for Postregsql. He showed some nice performance numbers and it was nice to see that they had gotten the coders who implemented the GiST indexing mechanisms to implement a GiST index for binary fingerprints.

In addition to these, there were other talks on Openbabel, Cinfony, Taverna, fpocket and others. While I’ve known about many of these projects it was useful to learn some of the details from the developers themselves.

A number of issues surrounding OSS development and use were discussed. For example, community development was regarded as a key factor in the success of OSS projects. Erik Lindahl of GROMACS fame, spoke about the development model of GROMACS and how important their success has been due to community involvement. Some other issues included the importance (and lack of) good documentation, what makes people contribute to OSS and so on.

The fact that industry participation was about 50% of group was nice. And a number of industry-related issues also arose. For example, there were several discussion of business models based around OSS and how they can feed back into OSS projects. A commen thread seemed to be that service and customization of OSS are good approaches to building businesses around the OSS stack, Silicos and Eagle Genomics being two prime examples.

The fact that there are industry users of OSS as well as industry members contributing back to OSS projects was very encouraging. An idea supported by a number of participants was some form of web site / wiki where such contributors and users could list themselves. (IMO, the Blue Obelisk wiki, could be a candidate for this type of thing).  Sure, there’d be usually corporate and legal barriers to this type of thing, but if done would have a number of benefits – encouragement for project developers and easily viewable precedent that would encourage other companies to use or participate in OSS projects, resulting in a positive feedback loop. With various pre-competitive collaboration efforts (e.g., Pistoia Alliance) popping up in the pharma industry, this is certainly possible.

Finally, it’s always good to meet up with old friends and also meet people whom I’ve only known over email. The social aspects of the workshop were very nice – helped greatly by excellent food and drink! Thanks to Mark for putting together a great meeting.

Written by Rajarshi Guha

May 6th, 2011 at 6:25 pm

Posted in cheminformatics

Tagged with , , ,

Drug-Target Networks & Polypharmacology

with 3 comments

I came across Takigawa et al where they address polypharmacology by investigating drug-target pairs.  Their approach is to simultaneously identify substructures from the ligand and subsequences from the target and combine this information to suggest drug-target pairs that represent some form of polypharmacology.  More specifically their hypothesis is that “polypharmacological principles” are embedded in a special set of paired fragments (substructures on the ligand side, subsequence on the target side). When you think about it, this is a more generalized (abstract?) version of a pharmacophore that makes the role of the target explicit.

Their approach originates from two assumptions

These results suggest that targets of promiscuous drugs can be dissimilar, implying that only a small part of each target is related with the principle of polypharmacology.


Similarly, recent research shows that smaller drugs in molecular weight are likely to be more promiscuous, suggesting that small fragments in each ligand would be a key to drug promiscuity

These lead to their hypothesis

… that paired fragments significantly shared in drug-target pairs could be crucial factors behind polypharmacology.

Based on this idea they first apply a frequent itemset algorithm to identify pairs of subgraph (SG) and subsequences (SS), that occur frequently (more than 5%) in the drug-target pairs. After identifying about 10,000 such SS-SG pairs, they define a sparse fingerprint, where each bit corresponds to one such pair. Using these fingerprints they then cluster the drug-target pairs, ending up with a selection of clusters. They then propose that individual clusters represent distinct polypharmacologies.

Our significant substructure pairs partitioned drug-target pairs covering most of approved drugs into clusters, which were clearly separated from each other, implying that each cluster corresponds to a unique polypharmacology type

While the underlying algorithms to obtain their results are nice, a lot of things weren’t clear.

Foremost, given the above quote, it’s not exactly clear from the paper what is meant by “unique polypharmacology type? Given that a cluster will consist of multiple drugs and multiple targets, it is not apparent from the text that a cluster highlights either promiscuity of compounds or ligand preferences for a small number of targets. While I think this is a major issue there are some other lesser problems

  • I get the impression that they consider promiscuity and polypharmacology as equivalent concepts. While there is a degree of similarity, I’d regard polypharmacology more as a rationally, controlled type of promiscuity
  • Most fragments they highlight in Figure 2 are relatively trivial paths. Certainly, reactive groups can lead to promiscuity; none of the subgraphs list exhibit reactive functionality and their application of the frequent itemset method, using a support of 5% could easily filter these out
  • Given they consider arbitrary subsequences of the target, the resulting associations could be meaningless. Again, it’d be interesting to note, in cases where crystal structure is available, how many of the subsequences, in the list of significant SS-SG pairs, lie in or around the binding site. A related question would be, of the SG-SS pairs associated with a cluster, how are individual subsequences distributed? Few unique subsequences could point towards a common binding site or active domain.
  • Related to the previous point, it’d be interesting to see in how many of the SG-SS paired fragments, the members correspond to actual interacting motifs (again based on crystal structure data).
  • One could argue that just using string subsequences to characterize the target misses information on important ligand-target interactions.

And while they may be the first to consider an analysis of drug-target pairs specifically, the idea of considering ligand and target simultaneously is not new. For example, the SiFT approach is quite similar and was described in 2004.

So, even though the paper seems pretty fuzzy on the supposed polypharmacology that they identify, it is overall an interesting paper (and one of the more interesting cheminformatics applications of frequent itemset methods).

Written by Rajarshi Guha

March 9th, 2011 at 6:07 am