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Cambridge MedChem Consulting

Innovate UK Opportunity to apply for a share of up to £20 million

Opportunity to apply for a share of up to £20 million to deliver game changing or disruptive innovations with significant potential for impact on the UK economy in partnership with Medicines Discovery Catapult.

More details here

Secure the funding you need to progress your projects towards commercialisation. Use our dedicated grant application team to ensure your submissions stand the best chance of success. Our experienced commercial and scientific teams have connections across industry, academia, finance, government, and research networks – we can help take your projects further towards commercial viability.

I've also compiled a page on Grant funded Research

Wellcome Trust £250m Leap Fund

Today Wellcome announced a new £250m not-for-profit fund: the Wellcome Leap Fund . The Leap Fund will accelerate discovery and innovation, with the aim of delivering breakthroughs over a five- to ten-year horizon.

"We want to take advantage of the surprising, left-field ideas that pose the question 'what if?' and support them in a new way that complements our existing funding structures."

Sounds like the aim is to support more high-risk research.

We don’t expect all projects to succeed, but we think the possibilities are incredibly exciting. And in taking some risks and backing at scale, we think we can deliver transformational developments that will improve people’s lives around the world

Wellcome have also recently announced the Open Research fund

Our new Open Research Fund supports innovative approaches that enable data, code or other research outputs to be discovered, accessed and reused

I've also compiled a page on Grant funded Research

How reliable is the literature?

In the past I've mentioned some of the concerns about antibody selectivity, the problems with irreproducible studies and the need for well characterised chemical probes. Elisabeth Bik has been looking at concerns with some of the images in the published literature, The prevalence of inappropriate image duplication in biomedical research publications. mBio 7(3):e00809-16. DOI. her Twitter feed contains yet more examples from the current literature, well worth a browse.

So completing this set, I looked at 101 papers, all published in the same month in the same journal. Of these, 63 contained photographic images (the others had only line graphs and/or tables). Of those, 8 have potential duplications. That is 12.7%

With all the advances in AI and image recognition I'm slightly disappointed that there is not a programme that can do this automatically for Elisabeth.


Macrocycles in the Protein Data Bank

The Protein Data Bank is an absolutely invaluable resource, the PDB is an archive of 3D structural information of proteins, nucleic acids, and bimolecular complex assemblies. However it is much, much more than a simple archive, the submitted structures are curated and annotated to add information about protein ID, sequence information, organism, ligand details etc. This allows users to interrogate the database in many different ways. The database currently holds 141209 entries, with over 10,000 new entries added every year. The vast majority are X-ray crystal structures but there are now over 12,000 NMR derived structures.

The PDB also contains 25626 chemical components - 24007 as free ligands in 106374 PDB file and you can search via a web interface or download the structures in sdf file format. However browsing through the downloaded file it was apparently that macrocycles were not well represented. A discussion with the extraordinarily helpful Rachel Kramer Green at PDB revealed the issue. Basically any ligand containing more that two amino-acids is treated as a protein not a ligand, there are other rules to deal with modified amino-acids etc. but the bottom line is that the only way to get a comprehensive view of macrocycles in the PDB is to download the entire PDB and programmatically by parsing the entire data set.

First we need to decide what size ring constitutes a macrocycle. asking the "internet" failed to produce a definitive answer.

macrocyclesize

You can read the results and download the script here.

pdbMacrocycles

There is also a page that discusses macrocycles in drug discovery.

There is also an upcoming meeting on Macrocycles, 3rd RSC BMCS Medicinal Chemistry Symposium on Macrocycles. Monday-Tuesday, 8th-9th October 2018, GlaxoSmithKline, Stevenage, UK. Full details are here http://www.maggichurchouseevents.co.uk/bmcs/Macrocycles-2018.htm. #BMCS_Macrocycles

The objective of this symposium is to promote scientific interaction between scientists with a shared interest in the field of Macrocycles. This area is responsible for a growing number of therapeutic approaches and development candidates, all of which go ‘beyond the rule-of–five’. As a researcher in this field, come along to hear about the latest advances and also to share in some of the secrets of discovering therapeutic agents which go beyond Lipinski’s rules.


Developing an assay for high-throughput screening

SULSA’s Assay Development Fund is actively recruiting innovative molecular targets for which there is a strong rationale for therapeutic potential.

Development of a high-throughput assay provide access to the various drug discovery initiatives that are available to the academic community, i.e. MRC DPFS, Bayer G4Targets, Wellcome Trust translational fund, the European Lead Factory, AZ innovation portal etc.

Drug Discovery Resources Updated

I've updated the Bioisosteres section adding a few more examples of aryl ring bioisosteres, and I've added CypReact to the predicting metabolism page.

arylNbioisostere

Macrocycles in Drug Discovery

I've created a new page in the Drug Discovery Resources section describing the use of macrocycles in drug discovery. With the advent of more challenging drug discovery targets such as protein-protein interactions there is renewed interest in molecules that are beyond the "Rule of 5". Macrocycles despite apparently undesirable physicochemical properties (High MWt, polar surface area etc.) can have good cell penetration and oral bioavailability.

cyclosporin

There is also an upcoming meeting on Macrocycles, 3rd RSC BMCS Medicinal Chemistry Symposium on Macrocycles. Monday-Tuesday, 8th-9th October 2018, GlaxoSmithKline, Stevenage, UK. Full details are here http://www.maggichurchouseevents.co.uk/bmcs/Macrocycles-2018.htm. #BMCS_Macrocycles

The objective of this symposium is to promote scientific interaction between scientists with a shared interest in the field of Macrocycles. This area is responsible for a growing number of therapeutic approaches and development candidates, all of which go ‘beyond the rule-of–five’. As a researcher in this field, come along to hear about the latest advances and also to share in some of the secrets of discovering therapeutic agents which go beyond Lipinski’s rules.

Pitfalls to avoid when building a Computational Therapeutics Company

 

Everyday I seem to hear about another tech company moving into healthcare, whilst I'm certain that Artificial Intelligence and Machine Learning has the potential to make a significant impact this advice should be compulsory reading for all involved.

https://a16z.com/2018/04/30/building-therapeutics-startups/

Drug Discovery Resources Updated

I've made a few additions and updated to the Drug Discovery Resources pages. In particular I've updated the covalent inhibitors page and added additional examples to the molecular interactions page. I've also started updating the ADME section and added a page on half-life and how it might be modulated.

repeated

Molecular Interactions page updated

I've updated the molecular interactions page to add more details on halogens.

Halogens are present in around 25% of drugs, calculated using data from Guide to Pharmacology Database and often used as bioisosteric replacements for H, Methyl, OH and NH2.

Bonds to halogen are significantly weaker than hydrogen bonds but there are many examples in the PDB of carbonyls interacting with halogens with bonds to I, and Br predominating. It is perhaps worth noting that halogens have been introduced into ligands to aid X-ray analysis, but they may also influence binding. Based on the observed bond angles the interaction is between the halogen and pi-cloud of the carbonyl rather than the lone pair with a clear clustering of X--O=C-N dihedral angles of 90° associated with interactions that involve primarily the pi-system of the carbonyl.