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Cambridge MedChem Consulting

Precursor Chemicals list

When helping to enhance screening collections I'm sometimes asked to exclude "prohibited precursor chemicals", these are chemicals that might be used in the manufacture of illegal drugs.

The effective control of chemicals used in the illicit manufacture of narcotic drugs and psychotropic substances is an important tool in combating drug trafficking. These chemicals, known as ‘precursors’, also have legitimate commercial uses as they are legally used in a wide variety of industrial processes and consumer products, such as medicines, flavourings and fragrances.

I'm aware of this list on the UK Government website, and the listing from INCB, however I'm sure it far from complete.

Does anyone know of a more complete listing? Preferably in a chemically intelligent form.

The SARS-CoV-2 main protease as drug target

A very useful primer for those interested in contributing to the ongoing research efforts at COVID moonshot and Open Source COVID-19.

The SARS-CoV-2 main protease as drug target DOI

The unprecedented pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening global health. The virus emerged in late 2019 and can cause a severe disease associated with significant mortality. Several vaccine development and drug discovery campaigns are underway. The SARS-CoV-2 main protease is considered a promising drug target, as it is dissimilar to human proteases. Sequence and structure of the main protease are closely related to those from other betacoronaviruses, facilitating drug discovery attempts based on previous lead compounds. Covalently binding peptidomimetics and small molecules are investigated. Various compounds show antiviral activity in infected human cells.

Remember a hit in a screen is just the very first step, there is much more to consider before it can be described as a drug candidate.

European Lead Factory Q&A

Interested in accessing a high quality high-throughput screening platform? Here is a chance to find out more about the European Lead Factory.

More details are here


The European Lead Factory (ELF) is a collaborative public-private partnership aiming to deliver novel lead molecules for drug discovery programs.

I've previously written about the ELF here.

Flatland: a nice place to be

As ever a useful analysis of the published literature on Practical Fragments, "Evaluation of 3-Dimensionality in Approved and Experimental Drug Space" DOI.

The true need for topological diversity in feedstocks and final drug molecules remains unclear given the overwhelming number of linear and planar drugs. The question remains as to whether more 3D compounds represent attractive and untapped therapeutic space, or if more linear/planar molecules are indeed the best topologies for bioactive molecules.

I came to a similar conclusion when looking at published fragment hits.

Drug Discovery Resources Website Stats

I wrote a blog entry about things that should be considered when proposing a hit identified from virtual screening as a drug candidate. Several people have suggested I create an easily identifiable web page so they can reference it. So here it is

COVID-19 and the Identification of "Drug Candidates".

I also thought I'd use the opportunity to look at the Drug Discovery Resources website stats for the first 6 months of 2020.

The Drug Discovery Resources pages are intended to act as a resource for scientists undertaking drug discovery, they were initially based on a course I give but have been expanded to give much more detail and to cover subjects not covered in the course.

The site has been viewed by almost 40,000 viewers with most people viewing a couple of pages per session. The viewers come from over 150 countries, the top countries being.

  • United States (28%)
  • United Kingdom (16%)
  • India (9%)
  • Germany (3.5%)
  • China (3%)
  • Canada (3%)
  • Japan (3%)

The most viewed pages were

Looking at the operating systems 55% are Windows users, 20% Mac users, 12% iOS and 12% Android, Chrome dominates the browser stats (64%) with Safari second (17%) and Firefox third (7%).

Another PYMOL session file

A full-length model of glycosylated SARS-Cov-2 spike protein is recently described in literature by Casalino et. al. The PDB files for models are available at These PDB files contain data for spike protein, glycans, lipid membrane, ions, and solvent.

Manish Sud has generated an annotated PyMol session file to view the model of spike protein present in open state conformation. The PyMOL session file is quite helpful during the reading of the article describing the work. It's a bit of elbow grease work to set up appropriate views in PyMOL and Manish has kindly shared it. It's available for download at I'm sure many will find it helpful.


The size of uncompressed PyMOL session file is quite large. It might take few minutes to load it into PyMOL, based on your hardware specifications.

Manish has also provided session files for SARS-CoV-2 Mpro ligands.

More COVID-19 MPro Activity Data

One of the best drug targets among coronaviruses is the main protease (Mpro), this enzyme is essential for processing the polyproteins that are translated from the viral RNA and the recognition sequence at most sites is Leu-Gln↓(Ser,Ala,Gly) and since no human enzymes have similar specificity inhibitors should be very specific. Mpro is a papain-like protease cysteine protease.

I've previously described the fragment hits from a fragment screen against crystals of the main protease (MPro) of SARS-CoV-2, the virus that causes COVID-19. Full details of the screening effort are described here

Additional biological results from project moonshot are now available. You can browse the data here

These results contain a significant milestone with the identification of the first sub micromolar non-covalent inhibitor.

JAG-UCB-a3ef7265-20 has been titrated twice now and has an IC50 of 0.6 uM.


This compound is a racemic mixture and the synthesis of the individual enantiomers is underway, if the activity predominantly lies with a single enantiomer we could see a further improvement in activity. The original submission was based on a pharmacophore search of Enamine based on amino-pyridine hits. I highlight this to underline the importance of simple descriptor-based searches, they are often highly competitive with sophisticated docking studies and require orders of magnitude less compute resources.

Since this research is being conducted in the public domain a number of other people have been able to contribute further ideas based on this exciting discovery.


21st RSC/SCI Cambridge MedChem Meeting

The first circular for the 21st Cambridge MedChem Meeting, 12-15th September 2021, Churchill College, Cambridge. #CamMedChem21

CMC - first announcement

Full details on the website.

GARDP: Bringing new treatments for drug-resistant infections to all who need them

This webinar provided an overview and update on GARDP’s efforts to bring new antibiotic treatments for drug-resistant infections to all who need them.

The following topics were presented:

  • Antibiotic resistance and the GARDP response
  • Tackling the growing threat of hospital infections
  • Developing new treatments for neonatal sepsis

Dexamethasone shown to reduce COVID-19 mortality

The NIHR-funded and supported study RECOVERY (Randomised Evaluation of COVid-19 thERapY) has announced that the steroid dexamethasone has been identified as the first drug to improve survival rates in certain coronavirus patients.

A total of 2104 patients were randomised to dexamethasone once per day for ten days and were compared with 4321 patients randomised to usual care alone. Among the usual care control group, 28-day mortality was highest in those on ventilators (41%), intermediate in those on oxygen only (25%), and lowest among those who were not receiving any respiratory intervention (13%).

The study, conducted at the University of Oxford and led by Professor Peter Horby and Professor Martin Landray, found that dexamethasone reduced the risk of dying by one-third in ventilated patients and by one fifth in other patients receiving oxygen only. There was no benefit among those who did not need respiratory intervention.

Dexamethasone is an inexpensive corticosteroid medication used to treat many inflammatory and autoimmune conditions, such as rheumatoid arthritis and bronchospasm. Glucocorticoids are part of the feedback mechanism in the immune system, which modulates certain aspects of immune function. They bind to the glucocorticoid receptor, and the activated complex up-regulates the expression of anti-inflammatory proteins and represses the expression of proinflammatory proteins.


Dexamethasone CHEMBL384467 has good oral bioavailability (80-90%) and a reasonable half-life (4 h), with a high volume of distribution (> 50L). It is also available as a 3.3 mg/mL solution for intravenous use. Dexamethasone is extensively metabolised to 6-hydroxydexamethasone via CYP3A4 mediated oxidation.

The oral LD50 in female mice is reported to be 6.5g/kg.