Filtering promiscuous compounds in early drug discovery: is it a good idea?

This is the question posed by the authors of a recent Drug Discovery Today article (Senger et al, Drug Discovery Today, article in press ). On first reading the question the instant answer from most practising medicinal chemists is surely yes, however the authors make some very good points that eliminating certain groups such as indoles from screening collection is somewhat short sighted or just simply wrong. On the other hand the authors do make some rather surprising and possibly naïve statement such as the recommendation to include quinone structures in phenotypic screening collections, an experienced medicinal chemist would argue there is simply no point testing them as they will be active anyway!

The article highlights the difference between classical biochemical screening with the objective of identifying hits which are active against a single target and phenotypic screening where the objective is to identify functionally active compounds irrespective of their mechanism of action. The authors propose that the now popular PAINS filters (Nature 2014, 513, 481-483) are appropriate for biochemical screening but should not be applied to compound collections used for phenotypic screening. They highlight a number of examples of structural types which are present in known drugs but would be removed by applying PAINS filters for example quinones (table 1). It is true that there are many quinone containing drugs on the market, but it is difficult to agree with the recommendation that even in phenotypic screens such compounds should be included. The compounds simply work by scavenging electrons and given the number of marketed drugs that contain quinones there is little need for more. Perhaps the only justification is to include marketed drugs in phenotypic screening collections with a view to future repositioning.

.pault Table1

A second set of problematic compounds highlighted as potentially useful are acyl hydrazones. Most medicinal chemists would not agree with the recommendation to include these in  screening collections as whilst there are examples of drugs (fig 1) which contain this group such functionality brings with it so many potential issues during development (genetoxicity, chemical instability, metabolism to a reactive hydrazine and many more) that they are best avoided in the first place.



Despite the recommendation to consider unattractive groups such as quinones and acyl hydrazones in phenotypic assays the third set of compounds highlighted by the authors is very sensible and prompts the question are filters in some cases too strict? The authors highlight indoles are privileged scaffolds. Indoles occur widely in marketed drugs they are chemically inert and generally safe. There are reports that certain indoles can form reactive metabolites – but this is true of any scaffold and is certainly not a reason to remove them from screening collections.

This is an interesting and thought provoking article and whilst it makes some interesting suggestions rightly challenges current thinking on the composition of screening collections. Drug discovery organisations are very risk averse these days some would say too risk averse. Whilst there are certain functionalities that should never appear, removing too many structural types can limit diversity and ultimately lead to a reduced chance of success in all modes of screening.

Blog wiritten by Paul Beswick

1 thought on “Filtering promiscuous compounds in early drug discovery: is it a good idea?

  1. There is also the question as to whether PAINS are genuinely promiscuous or simply quenching/scavenging singlet oxygen. The original PAINS definitions were based on analysis of output from 6 HTS campaigns all of which use AlphaScreen as for detection of ‘activity’ so it’s pushing things a bit to claim ‘pan assay interference’ behavior for the the offending literature polluters. I have linked the first of a three part series of blog posts as the URL for this comment and there are next/previous links at top of each post.

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