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Trying to squeeze sense out of chemical data

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What Has Cheminformatics Done for You Lately?

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Recently there have been two papers asking whether cheminformatics or virtual screening in general, have really helped drug discovery, in terms of lead discovery.

The first paper from Muchmore et al focuses on the utility of various cheminformatics tools in drug discovery.  Their report is retrospective in nature where they note that while much research has been done in developing descriptors and predictors of various molecular properties (solubility, bioavilability etc), it does not seem that this has contributed to increased productivity. They suggest three possible reasons for this

  • not enough time to judge the contributions of cheminformatics methods
  • methods not being used properly
  • methods themselves not being sufficiently accurate.

They then go on consider how these reasons may apply to various cheminformatics methods and tools that are accessible to medicinal chemists. Examples range from molecular weight and ligand efficiency to solubility, similarity and bioisosteres. They use a 3-class scheme – known knowns, unknown knowns and unknown unknowns corresponding to methods whose underlying principles are whose results can be robustly interpreted, methods for properties that we don’t know how to realistically evaluate (but which we may still do so – such as solubility) and methods for which we can get a numerical answer but whose meaning or validity is doubtful. Thus for example, ligand binding energy calculations are placed in the “unknown unknown” category and similarity searches are placed in the “known unknown” category.

It’s definitely an interesting read, summarizing the utility of various cheminformatics techniques. It raises a number of interesting questions and issues. For example, a recurring issue is that many cheminformatics methods are ultimately subjective, even though the underlying implementation may be quantitative – “what is a good Tanimoto cutoff?” in similarity calculations would be a classic example.  The downside of the article is that it does appear at times to be specific to practices at Abbott.

The second paper is by Schneider and is more prospective and general in nature and discusses some reasons as to why virtual screening has not played a more direct role in drug discovery projects. One of the key points that Schneider makes is that

appropriate “description of objects to suit the problem” might be the key to future success

In other words, it may be that molecular descriptors, while useful surrogates of physical reality, are probably not sufficient to get us to the next level. Schneider even states that “… the development of advanced virtual screening methods … is currently stagnated“. This statement is true in many ways, especially if one considers the statistical modeling side of virtual screening (i.e., QSAR). Many recent papers discuss slight modifications to well known algorithms that invariably lead to an incremental improvement in accuracy. Schneider suggests that improvements in our understanding of the physics of the drug discovery problem – protein folding, allosteric effects, dynamics of complex formation, etc – rather than continuing to focus on static properties (logP etc) will lead to advances. Another very valid point is that future developments will need to move away from the prediction or modeling of “… one to one interactions between a ligand and a single target …”  and instead will need to consider “… many to many relationships …“. In other words, advances in virtual screen will address (or need to address) the ligand non-specificity or promiscuity. Thus activity profiles, network models and polyparmacology will all be vital aspects of successful virtual screening.

I really like Schneiders views on the future of virtual screening, even though they are rather general. I agree with his views on the stagnation of machine learning (QSAR) methods but at the same time I’m reminded of a paper by Halevy et al, which highlights the fact that

simple models and a lot of data trump more elaborate models based on less data

Now, they are talking about natural language processing using trillion-word corpora. Not exactly the situation we face in drug discovery! But, it does look like we’re slowly going in the direction of generating biological datasets of large size and of multiple types. A recent NIH RFP proposes this type of development. Coupled with well established machine learning methods, this could be lead to some very interesting developments. (Of course even ‘simple’ properties such as solubility could benefit from a ‘large data’ scenario as noted by Muchmore et al).

Overall, two interesting papers looking at the state of the field from different views.

Written by Rajarshi Guha

April 5th, 2010 at 4:33 am

Simple XML Parsing with Clojure

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A while back I had started playing with Clojure. It’s always been a spare-time hobby and not having had much spare time I haven’t really gotten as far ahead with it as I’d have liked. I’m still not sure why I like Clojure, but it is fun to code in. My interest was revitalized when I came across a Clojure group located in the D.C. area. So following on my previous post on geo-referencing PubMed articles, I decided to take a stab at doing the whole thing in Clojure.

One of the tasks in this project is to query PubMed using the EUtils CGIs and parse out the information from the XML document that is returned. It turns out that parsing XML documents or strings is very easy in Clojure.  The parse method in the clojure.xml namespace supports parsing of XML documents, returning a tree of tags. Using xml-zipper from the namespace creates a zipper data structure from the tree. Extracting specific elements is achieved by filtering the zipper by the path to the desired element. It’s a lot like the ElementTree module in Python (but doesn’t require that I insert namespaces before each and every element in the path!). We start of by working in our own namespace and then importing the relevant packages

(ns entrez
  (:require [clojure.xml :as xml])
  (:require [ :as zip])
  (:require [ :as zf]))

Next we define some helper methods

(defn get-ids [zipper]
  "Extract specific elements from an XML document"
  (zf/xml-> zipper :IdList :Id zf/text))

(defn get-affiliations [zipper]
  "Extract affiliations from PubMed abstracts"
  (map (fn [x y] (list x y))
       (zf/xml-> zipper :PubmedArticle :MedlineCitation :PMID zf/text)
       (zf/xml-> zipper :PubmedArticle :MedlineCitation :Article :Affiliation zf/text)))

Finally, we can get the ID’s from an esearch query by saving the results to a file and then running

(println (get-ids
       (xml/parse "esearch.xml"))))

or extract affiliations from a set of PubMed abstracts obtained via an efetch query

(println (get-affiliations
       (xml/parse "efetch.xml"))))

In the next post I’ll show some code to actually perform the queries via EUtils so that we don’t need to save results to files.

Written by Rajarshi Guha

February 17th, 2010 at 3:30 am

Posted in software,Uncategorized

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When is a Bad Plate Bad?

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When running a high-throughput screen, one usually deals with hundreds or even thousands of plates. Due to the vagaries of experiments, some plates will not be ervy good. That is, the data will be of poor quality due to a variety of reasons. Usually we can evaluate various statistical quality metrics to asses which plates are good and which ones need to be redone. A common metric is the Z-factor which uses the positive and negative control wells. The problem is, that if one or two wells have a problem (say, no signal in the negative control) then the Z-factor will be very poor. Yet, the plate could be used if we just mask those bad wells.

Now, for our current screens (100 plates) manual inspection is boring but doable. As we move to genome-wide screens we need a better way to identify truly bad plates from plates that could be used. One approach is to move to other metrics – SSMD (defined here and applications to quality control discussed here) is regarded as more effective than Z-factor – and in fact it’s advisable to look at multiple metrics rather than depend on any single one.

An alternative trick is to compare the Z-factor for a given plate to the trimmed Z-factor, which is evaluated using the trimmed mean and standard deviations. In our set up we trim 10% of the positive and negative control wells. For a plate that appears to be poor, due to one or two bad control wells, the trimmed Z-factor should be significantly higher than the original Z-factor. But for a plate in which, say the negative control wells all show poor signal, there should not be much of a difference between the two values. The analysis can be rapidly performed using a plot of the two values, as shown below. Given such a plot, we’d probably consider plates whose trimmed Z-factor are less than 0.5  and close to the diagonal. (Though for RNAi screens, Z’ = 0.5 might be too stringent).

From the figure below, just looking at Z-factor would have suggested 4 or 5 plates to redo. But when compared to the trimmed Z-factor, this comes down to a single plate. Of course, we’d look at other statistics as well, but it is a quick way to rapidly identify plates with truly poor Z-factors.

A plot of Z-factor versus trimmed Z-factor for a set of 100 plates

A plot of Z-factor versus trimmed Z-factor for a set of 100 plates

Written by Rajarshi Guha

January 29th, 2010 at 5:47 pm

A Custom Palette for Heatmaps

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Heatmaps are a common way to visualize matrices and R provides a variety of methods to generate these diagrams. One of the key features of a heatmap is the color scheme employed. By default the image method uses heat.colors which ranges from red (lowest values) to white (highest values). Other palettes include rainbow and topographical. However, I needed to replicate a color scheme used in a previous publication – dark red for low values and white for high values, passing through shades of pink. While RColorBrewer is an extremely useful package for generating sensible and informative color schemes it didn’t help me out here – the red palette was limited to 9 colors, whereas I needed a larger range. There’s also the colorschemes method from the ClassDiscovery package, but I haven’t checked that out.

So, I ended up making my own color scheme, realizing that shades of pink are a constant red, coupled with increasing amounts of blue and green (in the RGB scheme). Thus generating a matrix of R, G and B values, with a constant red value and increasing blue and green values and then converting the rows to hex colors (via rgb, gives me the required colors.

rgbs <- cbind(255,
                     seq(32,255, length=256),
                     seq(32,255, length=256)) / 255
cols <- rgb(rgbs[,1], rgbs[,2], rgbs[,3])

and an example of the color scheme

image(matrix(1:256, nrow=64, byrow=TRUE),

resulting in

Written by Rajarshi Guha

October 28th, 2009 at 1:26 pm

Posted in research,Uncategorized

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Oracle Notes

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Some handy settings when running a query from the command line via sqlplus

set echo off
set heading on
set linesize 1024
set pagesize 0
set tab on
set trims on
set wrap off
-- might want to set column formats here
-- e.g.: column foo format A10
spool stats -- dump results to stats.lst
-- SQL query here

spool off

Written by Rajarshi Guha

October 6th, 2009 at 2:26 pm

Posted in Uncategorized

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