Something rare nowadays – a publication

As life continues after my years of research in R&D, there are and will be less and less publications. Therefore I am even more so excited and happy if I can contribute to some great scientific work.

Alf Claesson, the main author, and I have published a “Perspective” in the ACS journal Chemical Research in Toxicology, titled “Systematic Approach to Organizing Structural Alerts for Reactive Metabolite Formation from Potential Drugs”.

We believe it should be a good tool for especially medicinal chemists who design new compounds, but also for metabolic biologists who work with reactive metabolites. It has to do to some extend with the software SpotRM+ by Awametox which is to a certain extent the engine behind this paper.

Here is the full citation:

Systematic Approach to Organizing Structural Alerts for Reactive Metabolite Formation from Potential Drugs

Alf Claesson and Alexander Minidis
Chemical Research in Toxicology 2018 31 (6), 389-411

DOI: 10.1021/acs.chemrestox.8b00046

And the link:
https://pubs.acs.org/doi/10.1021/acs.chemrestox.8b00046

SpotRM+ – potential reactive metabolite formations – batch analysis in Knime

Modelling and prediction of toxicity of drug compounds has been, is, and will be be a continuous area of interest. I won’t go into the detailed literature of this, here, I want to focus on SpotRM+’s contribution to that field:
This methodology focuses on reactive metabolite formation and avoidance as a means to reduce structure based toxicity issues. In addition, it is a computationally cheap method since it is solely based on SMARTS, carefully hand-curated ones at that. In addition to identifying certain structural features, SpotRM+ delivers one to three page monographs on the marketed (or withdrawn) reference compounds including mechanistic summaries. So it is more about learning than pure black box filtration.

SpotRM+ requires Bioclipse, a platform which has chemical data-mining in its focus. There is a disadvantage to this package – you can only run and analyze one compound at a time, batch mode isn’t possible.
According to the company Awametox AB, the batch mode analysis is a feature requested by a number of customers, e.g. for design/synthesis prioritization. And yes, it is possible – IF you use script based or workflow based tools with one of the simpler ones being Knime. For this, you require access to the SpotRM+ database itself and the standard chemistry mining nodes in Knime.
[note that SpotRM+ is a commercial package, though there is a free demo available; both are based on Bioclipse. For the mining suggested here you need the database itself which can be purchased separately]

One of the drawbacks of the database and the SpotRM+ system with regards to batch analysis is that it isn’t really designed for batch analysis. The readout usually consists of a traffic light colouring system of reference compounds and links to their analysis monographs. Thus, for batch mode to work, you need to ask what you desire of it -e.g.

  • Is a single “red” or “green” reference hit sufficient?
  • Do you want to summarize all the reference hits?
  • Combine with other data for further calculations?

In principle, anything goes, that’s the beauty of the flexibility of a package such as Knime. But, would that be sufficient for you to make a decision? I can imagine that a batch based “high quality” decision should be possible, if you combine the output with, e.g., a model based on measured ADMET data (and/or reactive metabolite data).
Independent of the latter, a basic workflow could look simply like this:


You can find more info and access to mentioned programs here:
SpotRM+:   www.awametox.com (bioclipse included; recently updated to V1.2!)
Bioclipse:   www.bioclipse.net (mainly for info, not required to download separately)
Knime:   www.knime.org