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Cambridge MedChem Consulting

Seasons Greetings

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Clare College view of bridge from Old Court

As in previous years all monies saved for not sending greetings cards will be given to the Multiple Sclerosis Society

Cancer-causing mutation suppresses immune system around tumours

Interesting report from the Crick. Mutations in 'Ras' genes, which drive 25% of human cancers by causing tumour cells to grow, multiply and spread, can also protect cancer cells from the immune system. They show that mutated Ras genes can suppress the immune system around tumours by increasing levels of a protein called Programmed death-ligand 1 (PD-L1). It was already known that high expression levels of PD-L1 was associated with increased tumour aggressiveness and an increased risk of death, and the current study provides the mechanism.

Open Access DOI

Several PD-L1 inhibitors are in development, including Atezolizumab.

Open Source Malaria, what to make next

The Open Source Malaria project is trying a different approach to curing malaria. Guided by open source principles, everything is open and anyone can contribute.

A recent post gives an opportunity for everyone to participate, you can read a description of the background here Poll to decide which compounds to synthesise next as 'Pfizer phenol' analogues and the actual poll is here.

Following on from @JoshMaxwell's introductory post #554, we're keen to continue exploring this chemistry which now appears to be working well, and applying it to make further analogues of the phenol compound OSM-S-412, OpenSourceMalaria/Series4#3.

You should of course feel free to suggest additional modifications, it would be particularly useful if you could include a brief comment as to why you think your suggestion might be interesting.

D3R Grand Challenge 2: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

The Drug Design Data Resource (D3R) is an NIH-funded resource dedicated to improving method development in ligand docking and scoring through community-wide blinded prediction challenges (http://www.drugdesigndata.org). DOI

The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total. Procedurally, GC2 mimicked Grand Challenge 2015 (GC2015), with a Stage 1 sub-challenge testing ligand pose prediction methods and ranking and scoring methods, and a Stage 2 sub-challenge testing only ligand ranking and scoring methods after the release of all blinded co-crystal structures. Two smaller curated sets of 18 and 15 ligands were developed to test alchemical free energy methods. This overview summarises all aspects of GC2, including the dataset details, challenge procedures, and participant results. We also consider implications for progress in the field, while highlighting methodological areas that merit continued development. Similar to GC2015, the outcome of GC2 underscores the pressing need for methods development in pose prediction, particularly for ligand scaffolds not currently represented in the Protein Data Bank (http://www.pdb.org), and in affinity ranking and scoring of bound ligands.

Conclusions:

  • Successful prediction of ligand–protein poses depends on the entire workflow, including factors extrinsic to the core docking algorithm, such as the conformation of the protein selected.
  • The accuracy of pose predictions tends to be improved by the use of available structural data, via ligand overlays and/or selection of receptor structures solved with similar ligands.
  • The accuracy of the poses used in structure-based affinity rankings does not clearly correlate with ranking accuracy.
  • Explicit solvent free energy methods did not, overall, pro-vide greater accuracy than faster, less detailed scoring methods

Kinase Inhibitor Landscape

With over 500 proteins encoded in the human genome it is perhaps not surprising that among enzyme inhibitors, Kinase inhibitors are an increasingly important therapeutic category. The plot below the number of results returned for various string searches of PubMed versus year. Whilst "serine protease inhibitors' (grey) was the highest scoring in 1995 over the intervening years "kinase inhibitors" (red) has risen and is now the highest scoring search string.

stringsearches

Given that many of the inhibitors target the ATP binding site it is perhaps not surprising that many molecules inhibit multiple kinases, unfortunately this information is not in a readily searchable format. A recent publication "The target landscape of clinical kinase drugs" DOI describes an approach to provide better understanding

To this end, we used a chemical proteomic approach (kinobeads) and quantitative mass spectrometry to characterize the target space of 243 clinical KIs that are approved drugs or have been tested in humans…..The number of targets for a given drug differed substantially. Whereas some compounds showed exquisite selectivity, others targeted more than 100 kinases simultaneously, making it difficult to attribute their biological effects to any particular mode of action.

All drug profiles can be interactively explored in ProteomicsDB and a purpose-built shinyApp.

opnMe Chemical probes from Boehringer Ingelheim

One of the key challenges to exploring interesting targets is having access to high quality molecular probes. A number of organisations have go together to support Chemical Probes Portal which provides information and independent reviews of chemical probes.

The Chemical Probes Portal is designed to change the way scientists find and use small-molecule reagents called chemical probes in biomedical research and drug discovery. The Portal is backed by reviews and commentary from recognised chemical probe experts. Our knowledge-dissemination model, focused on providing accessible expert advice, promises to increase research reproducibility, maximise investment outcomes and accelerate the discovery science that informs the next generation of therapeutic

Recently Boehringer Ingelheim have decided to provide access to a number of chemical probes.

To foster innovation, Boehringer Ingelheim (BI) is openly sharing selected molecules with the scientific community to unlock their full potential. There are two types of Boehringer Ingelheim molecules that you can access on this portal: some for ordering, some for collaboration.

These molecules cover a range of interesting molecular targets.

Target ID
Aurora B inhibitor BI 831266
Autotaxin (ATX) inhibitor BI-2545
BCL6 degrader BI-3802
BCL6 inhibitor BI-3812
CCR1 antagonist BI-9667
CCR10 antagonist BI-6901
CDK8 inhibitor BI-1347
FAS inhibitor BI 99179
FLAP antagonist BI 665915
Glucocorticoid Receptor (GR) Agonist BI 653048
Hep. C virus (HCV) NS5B polymerase inhibitor BI 207127 (Deleobuvir)
Hepatitis C virus (HCV) NS3 protease inhibitor BI-1230
Hepatitis C virus (HCV) NS3 protease inhibitor BI-1388
LFA-1 (lymphocyte function-associated antigen-1) antagonist BI-1950
NHE1 inhibitor BI-9627
PLK1 inhibitor BI-2536
sEH inhibitor BI-1935
SYK inhibitor BI 1002494

Looking at the selective Aurora B kinase inhibitor BI 831266, it is clear that BI is making available high quality molecules, they provide the structure, in vitro activity, together with both in vitro and in vivo DMPK data in multiple species. They also suggest a related compound as a negative control in which the N-Me serves to block the critical hinge binding.

BIcompounds

There is also a co-crystal structure and some counter-screening data, together with key references from the literature. Any data generated can be published without approval from BI.

This looks to be a very exciting initiative and it will be interesting to see if other companies follow suit.

They have also created a search engine BI Miner to search multiple data sources simultaneously (PubMed Central, Medline, Patents, Drug labels, Expression Data, NIH Grants, Clinical Trials), this open access.

biminer

Determining plasma protein binding

Since the Drug Discovery Resources page on Distribution and Plasma Protein Binding is one of the most frequently read I thought I'd mention a publication from the Univ of Washington DOI describing an inexpensive Microdialysis Device for Measuring Drug–Protein Binding (DIYM).

The device is based on the standard equilibrium dialysis method to measure the fraction of low molecular weight compound bound to proteins. It is constructed from a standard polypropylene 96-well plate, dialysis tubing, and low viscosity epoxy resin. The device can be readily prepared for a small fraction of the cost of a commercial, multi-chamber, micro-dialysis device.

The results obtained agree favourably with literature values.

Compound DIYM (%) Lit (%)
Dextromethorphan 66.8 65
Diclofenac 98.0 99.5
Mefloquine 98.9 >98
Methotrexate 54.0 50.4
Paclitaxel 94.2 95
Progesterone 97.0 98
Propranolol 82.5 82
Testosterone 93.3 98

Trim-Away

A new way to deplete endogenous proteins, Trim-Away a technique to degrade endogenous proteins acutely in mammalian cells without prior modification of the genome or mRNA. Trim-Away harnesses the cellular protein degradation machinery to remove unmodified native proteins within minutes of application.

We reasoned that the antibody receptor and ubiquitin ligase TRIM21 could be used as a tool to drive the degradation of endogenous proteins by using a 3-step strategy: first, the introduction of exogenous TRIM21; second, the introduction of an antibody against the protein of interest; and third, TRIM21-mediated ubiquitination followed by degradation of the antibody-bound protein of interest.

There is more information on the MRC website

I've added it to the Target Validation page.

NAR Database Issue

The Nucleic Acid Research Database Issue is now available. Details of over 600 databases described in open access publications.

m_gkw1338fig2

These databases cover a huge area of biological science, including:-

  • Nucleic acid sequence, structure, and regulation
  • Protein sequence and structure, motifs, and domains
  • Metabolic and signalling pathways, enzymes
  • Viruses, bacteria, protozoa and fungi
  • Human genome, model organisms, comparative genomics
  • Genomic variation, diseases, and drugs
  • Plant databases

Neglected and Tropical Diseases Session at the 19th Cambridge MedChem Meeting

Update

I'm delighted to report that over 200 people have now watched the video online, looks like it was a valuable resource.


One of the nice things about my job is I get the chance to take part in some truly inspiring events. Last month I had the honour of chairing a session on Neglected and Tropical Diseases at the 19th Cambridge MedChem Meeting. In an effort of extend the exposure of the brilliant science undertaken in this important therapeutic area the conference organisers arranged for this to be a live webinar. The session was also recorded and is now available online.

https://youtu.be/XLOCFrjrMEY

This is a recording of the Neglected and Tropical Diseases Session at the 19th Cambridge MedChem Meeting, 11-13 September 2017. The speakers are Kelly Chibale (Univ of Capetown), Christoph Boss (Actelion), Rob Young (GlaxoSmithKline), Jonathan Large (LifeArc) and Charles Mowbray (DNDI).

Please feel free to share. #19thCamMedChem.

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