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Cambridge MedChem Consulting

ADME pages updated

I've spent a while updating the ADME section of the Drug Discovery Resources. I particular I've added a little on the Developability score DOI that identifies four distinct cLog P/molecular weight regions that define optimal and sub-optimal chemical space. I've also added a couple of useful references.

In addition, I've expanded the Absorption and Bioavailability page to include more on bioavailability with links to physicochemical properties. The Distribution and Plasma Protein Binding section has a couple of extra examples demonstrating the impact plasma protein binding has on other pharmacokinetic properties. I've added a few details of in vitro assays to the Transporters page, and expanded the in silico brain penetration models section.

The section on Aldehyde oxidase has been greatly expanded and now includes a section on prediction and mitigation, and added useful references.



I've added a new entry on to the available fragments page, BioBlocks is a newcomer to the field of fragment collections. Whilst many collections are culled from available compound collections using calculated property filters (eg Rule of 3), BioBlocks have designed novel fragments and as such there is negligible overlap with other collections. One concern with bespoke fragments is that it is often a challenge to find related analogues for followup. The BioBlocks Comprehensive Fragment Library (CFL) is a subset generated from a >1 million member synthesizable virtual library, so follow up compounds can be generated using proven in house chemistry.


Practical Fragments Poll

The latest fragment-finding methods poll has been published on Practical Fragments.

The results underline the increase in the use of fragment based screening across the industry with 85% of the respondents now reporting that they actively use fragment screening. The technologies used to detect binding have also diversified with X-ray, NMR and SPR dominating. This mirrors my findings from published fragment hits. The choice of detection technology may be due to the additional structural information that X-Ray and NMR can offer.


I was delighted to see this comment,

For the first time we asked about use of literature to identify fragments, and nearly a third of respondents said they incorporate previously published fragments into their work. As the amount of publicly available information continues to increase it will be interesting to see whether this number grows.

I'll be updating the published fragment hits at the end of the year.

OpenTargets updated

Just had an email about the latest Open Targets Platform release - 19.11.

In this release there is data on

  • 27,069 targets
  • 13,579 diseases
  • 8.91 million pieces of evidence
  • 6.33 million associations between targets and diseases

20 Years of Rule of 5 Meeting Report

It has been over twenty years since Lipinski published his work determining the properties of drug molecules associated with good solubility and permeability. Since then, there have been a number of additions and expansions to these “rules”. There has also been keen interest in the application of these guidelines in the drug discovery process and how these apply to new emerging chemical structures such as macrocycles. This symposium brought together researchers from a number of different areas of drug discovery and provided a historical overview of the use of Lipinski’s rules, as well as looking to the future and how we use these rules in the changing drug compound landscape.


The 20 Years of the Rule of Five Meeting brought together researchers from a number of different areas of drug discovery and provided both a historical overview of the use of Lipinski’s rules, as well as looking to the future and how these rules might evolve in the changing drug compound landscape. The meeting had a capacity attendance of over 100, with Sygnature kindly providing the venue. The audience was a nice mix of industry “veterans”, students and those new to the industry. The meeting format was a morning session giving a historical viewpoint followed by a panel discussion, and the afternoon was dedicated by a more forward looking session again followed by a panel discussion.

The full report is here in PDF format Full Report, many thanks to the presenters for permission to use the images.

More details and the available slide decks are here, Twitter hashtag - #RuleofFive2019.

Call for Open Source Antibiotics Fragment Contributions

What we have: Fragment hits from an initial screen against MurE and MurD, performed at Diamond screening facility, and a platform to screen additional fragment libraries or follow-up compounds.

What we need: Additional chemical matter for screening. The Diamond screening platform is high-throughput and we would ideally be able to take full advantage of this.

Full details are on the Open Source Antibiotics website


Covalent Modification

I've written a page in the Drug Discovery Resources on covalent inhibitors.

This publication suggests this area is going to become more important "An activity-guided map of electrophile-cysteine interactions in primary human immune cells"

Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology.

European Lead Factory

Great news! European Lead Factory has restarted.

Pivot Park Screening Centre has successfully completed the first ultra-High Throughput Screening in IMI’s ESCulab project, and as such restarting the operations of the European Lead Factory. The screening on the European Compound Collection of ~500.000 compounds using a biochemical 1536-wells assay was finished within 4 days. Currently triaging of the UK owned program is ongoing within the Consortium, applying further biochemical and biophysical follow-up assays as well as the resynthesis of promising hits.

The programme is currently accepting proposals

First call for proposals to the Psychiatry Consortium

A new initiative, great to see efforts in CNS diseases.

First call for proposals to the Psychiatry Consortium. Read more about the kind of projects the Psychiatry Consortium is looking to fund on the website

Register here

History of rare diseases and their genetic causes - a data driven approach

One of the advantages of being a consultant is that I can feel free to contribute to projects that I find interesting. So as well as working with a couple of Open-Source drug discovery projects (e.g. Open Source Antibiotics I can also follow a couple of rare disease programs.

This publication looks very useful History of rare diseases and their genetic causes - a data driven approach.

This dataset provides information about monogenic, rare diseases with a known genetic cause supplemented with manually extracted provenance of both the disease and the discovery of the underlying genetic cause of the disease.

More details of how the dataset was constructed.

We collected 4166 rare monogenic diseases according to their OMIM identifier, linked them to 3163 causative genes which are annotated with Ensembl identifiers and HGNC symbols. The PubMed identifier of the scientific publication, which for the first time describes the rare disease, and the publication which found the gene causing this disease were added using information from OMIM, Wikipedia, Google Scholar, Whonamedit, and PubMed. The data is available as a spreadsheet and as RDF in a semantic model modified from DisGeNET.

A very interesting read.