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Cambridge MedChem Consulting

Emerging Technologies Competition

The Emerging Technologies Competition is the Royal Society of Chemistry’s annual initiative for early stage companies and academic entrepreneurs who want to commercialise their technologies to make a global impact.

They are seeking applications from entrepreneurs who are developing technologies that have a strong chemistry component and fall within one of the following categories:

  • Health
  • Food & Drink
  • Energy & Environment
  • Enabling Technologies

From the application round, 24 finalists are selected to present their technologies to a panel of judges. These judges then choose 4 winners (1 per category). Winners receive £20,000 and mentorship. Applications close 12 July 2020.

There are more details here https://www.rsc.org/competitions/emerging-technologies/

Fragments and novelty

I've spoken to a couple of people recently who are very focused on identifying novel fragments for their fragment screening collection. I have to say I'm not convinced about the benefit of populating your fragment collection with novel fragments. One of the really attractive features of fragment-based screening is the ability to follow up and verify the initial round of fragment hits by testing commercially available analogues, or isomers.

You can read more here Fragments and novelty.

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Full details of the Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease are now published. https://www.biorxiv.org/content/10.1101/2020.05.27.118117v1.full.pdf

An extraordinary effort highlighted by the timeline shown below.

COVIDfragmentScreen

The results of the first round of biological results from project moonshot are in. You can browse the data here https://postera.ai/covid/activity_data.

A listing of my posts on COVID-19 are here.

First round of MPro bioactivity results

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 https://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem/Downloads.html

The results of the first round of biological results from project moonshot are in. You can browse the data here https://postera.ai/covid/activity_data.

COVID_MProFirstresults

Most of the most active compounds are chloroketones or acrylamides, presumably covalent inhibitors, and they all show selectivity over Trypsin (IC50 >99 uM).

There are a few structures that look more like competitive inhibitors shown below

COVID_MProfirstresultsGrid

A number of these structures now have crystal structures available.

A sdf file containing these non-covalent structures is here

Fantastic work by all involved.

COVID-19 and the Identification of "Drug Candidates"

One of the really heartening things to come out of the current pandemic is the willingness of many scientists to put aside their own research and throw themselves into the efforts to find a treatment. However, lack of domain expertise is always a problem when scientists enter a new field, so I thought I'd put together a few things to consider.

In silico screening, for docking experiments you need to put considerable effort into ensuring the protein structure used is appropriate, you can't simply download a PDB file from the Protein Data Bank and use it. It will undoubtedly contain errors, you will need check protonation, hydrogen bonds etc. Then there is the issue of deciding which solvent molecules are important. Binding energies, docking scores are not as accurate as many seem to assume and no substitute for an experienced medicinal chemists looking at the bound poses, I've tried to summarise the types of molecular interactions here. Remember to also think about the impact of solvation. For other virtual screening approaches you need to be very careful about the quality of the input data. In many cases it will be heavily biased towards actives.

In silico predictions are no substitute for biological data, if you are using repurposed drugs or available chemicals there is really no excuse for not generating the appropriate in vitro biological data, there are many labs who would be happy to collaborate. If the molecules are novel many custom synthesis companies have offered to help. Remember that the IC50 is probably not that useful, it is likely that you will want to block the target 100% so you need to be above the IC95. In vitro biochemical assays using isolated enzymes will often give a false sense of potency, you should also determine activity in a cell-based assay in the presence of plasma.

If you are proposing a repurposed drug there will be a lot of information about the drug in the public domain, you may well need to search for compound codes, and various drug name synonyms. UniChem is a very useful web service for cross-referencing between chemical structure identifiers.

There are now many free, web-accessible databases some useful starting points are shown in the table below.

Name Link Description
ChEMBL https://www.ebi.ac.uk/chembl/ A database of bioactive drug-like small molecules, it contains 2-D structures, calculated properties (e.g. logP, Molecular Weight, Lipinski Parameters, etc.) and abstracted bioactivities (e.g. binding constants, pharmacology and ADMET data).
PubChem https://pubchem.ncbi.nlm.nih.gov Three linked databases within the NCBI's Entrez information retrieval system. These are PubChem Substance, PubChem Compound, and PubChem BioAssay. Many compounds have links to primary literature and patents
Guide to Pharmacology https://www.guidetopharmacology.org/GRAC/searchPage.jsp An expert-driven guide to pharmacological targets and the substances that act on them.
DrugBank https://www.drugbank.ca The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug data with comprehensive drug target information
NCI Thesaurus https://ncithesaurus.nci.nih.gov/ncitbrowser/ NCI Thesaurus (NCIt) provides reference terminology for many NCI and other systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities
Clinical Trials https://clinicaltrials.gov A database of privately and publicly funded clinical studies conducted around the world
FDA https://www.fda.gov Food and Drug Administration responsible for safety and efficacy of drugs
WIPO https://www.wipo.int/portal/en/index.html World IP services

Find out the original target and mode of action. I've seen a couple of proposed compounds that are known prodrugs, the parent compound is designed to either breakdown or be modified in vivo to yield the active compound. The prodrug may have negligible systemic exposure. Covalent modifiers may look attractive but selectivity is always a concern and they may have narrow therapeutic windows.

Look at the original indication, many anticancer drugs are extremely toxic and could not be given other patients. Similarly, drugs that reduce blood pressure or other physiological changes may be problematic. You may well be able to find counter-screening data, this could highlight problematic off-target activities.

Look at the approved dosing regime, if a drug is only approved for doses of 2 ug/kg there might well be good reasons, and if your proposed drug only has uM activity in the in vitro assays you won't be able to generate sufficient plasma concentrations. Check what safety studies have been undertaken, are they sufficient to support multi-day dosing?

Look at the pharmacokinetics, you should be able to model the dosing regime needed to maintain plasma concentrations above IC95, this will may need to be maintained 24 hours a day. Check protein binding and distribution and use in the predictive modelling.

plasmaconcs

Look for the routes of administration, for in intensive care I suspect many will need the drug to be administered i.v. if there is no intravenous formulation is the drug soluble enough for one to be developed, ber in mind the limitations of intravenous formulations

Many of the patients will be on multiple drugs, both to treat the viral infection but also adventitious bacterial infections and since many are elderly and have pre-existing medical conditions they may have a cocktail of drugs prescribed. Drug-Drug interactions thus become a major concern, any proposed drug to treat the virus that has major interactions with CYP450 enzymes (induction, inhibition or metabolism) is likely to hugely complicate the overall dosing regime.

Check for any toxicity information, particularly black box warnings. HERG inhibition and QT prolongation is an issue that most drug discovery projects have to address at some point. This is particularly worrying if coupled with potential drug-drug interaction described above. You should also be able to find the data from safety studies, these may describe the dose limiting toxicities.

All of this information should be in the public domain, and if you are proposing a compound as a "Drug Candidate" you should not be expecting someone else to pull it all together to decide whether it is worth pursuing clinically.

Updated 26 April 2020

This Week in Virology

An interesting weekly podcast that is currently topical.

This week Doris Cully joins TWiV to discuss inhibition of SARS-CoV-2 in cell culture by ivermectin.

https://podcasts.apple.com/podcast/id300973784

COVID-19 Registered Trials

There are now a number of clinical trials underway and this review by The Centre for Evidence-Based Medicine provides an excellent summary of the trials that are taking place. They describe proposed pharmacological interventions and their mechanisms, when known, but unfortunately don't give the chemical structures.

Updated

I've also now included a few other structures that people have sent to me.

Here is the workflow I use to get the structures and access more information about the compounds.

Create a text file with all the structures mentioned

ASC09
Azvudine
Azithromycin
Baloxavir
Carriomycin
Chloroquine
cobicistat
Danoprevir
Darunavir
Dihydroartemisinin
Favipiravir
Fingolimod
hydroxychloroquine
Jakotinib
Leflunomide
Lopinavir
marboxil
Methylprednisolone
oseltamivir
piperaquine
Remdesivir
ribavirin
ritonavir
Ruxolitinib
Suramin
Thalidomide
thymosin
Triazavirin
Umifenovir

Now read the text file into Vortex

covidTrialstext

The use a Name to Structure script to use a web service to get the structures, in this case I used ChemSpider. Now generate the InChiKey from the structures.

covidstructures

We can now use the InChiKey to search UniChem using another Vortex script to get identifiers for the molecule from various databases.

UniChem efficiently produces cross-references between chemical structure identifiers from different databases

updatedcovidstructures

We can then use the identifiers to search the various databases for more information

I've been asked if I could provide the structures for download

Here it is in SDF file format http://cambridgemedchemconsulting.com/news/files/COVID19/coviddata.sdf.zip

And in SMILES format http://cambridgemedchemconsulting.com/news/files/COVID19/forpost.smi.zip.

The quality of the crystal structure is critical

Crystal structures are not perfect, and it is important to understand the limitations and not assume as Derek Lowe once put it, they are a "message from God". It might be worth reading the section on structure-based design.

With this in mind I thought I'd flag this message from Bobby Glen (Cambridge) here.

Hi, we’re still (Jason at CCDC) porting GOLD to our HPC system so we can basically parallel dock. We should be able to dock and score early next week I hope, There are a few issues we also are addressing wrt the crystal structures, Gerard Bricogne at Global Phasing is kindly re-refining the published structure from the ED, this hopefully will inform us of for making some changes to the orientation/pKa and tautomers of the histidines and some of the other AAs. It’s very difficult to ‘see’ hydrogen in x-ray and these are inferred from the structure. We need to be sure we have a decent model of this (at physiological pH) before doing all the calculations. An example is H163, which is in the binding site, and is critical to a few of the interactions seen in ligands for this class of proteases. Automated hydrogen addition can be problematic.

News categories Updated

The News Categories provides a means to rapidly find new articles and update information on this site.

There has been a significant increase in several categories so I've updated the page.

For example:

COVID-19

Coronavirus

Help design inhibitors of the SARS-CoV-2 main protease

Are you a medicinal chemist currently locked out of your lab?

Why not take a break from writing papers/reports and lend your expertise to this effort, https://covid.postera.ai/covid. They have identified 60 fragment hits and are asking for insight in what should be made next.

We are now asking for your help in designing new inhibitors based on these initial fragment hits: the exceptionally dense readout suggests countless opportunities for growing and merging, and we need many sharp brains to sift through them; it is also what makes us believe that potency can be directly achieved.

The first round of submissions will be reviewed tonight and the selected molecules will be made by Enamine.