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Cambridge MedChem Consulting

Seasons Greetings

SeasonsGreetings

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

Another Chemical Probe

Boehringer Ingelheim have made a new addition to opnMe their portal for free chemical probes.

To foster innovation, we openly share selected molecules with the scientific community to unlock their full potential - all for free, no hidden costs.

The latest addition is a potent Chymase inhibitor, Chymase is a chymotrypsin-like serine protease that is stored in a latent form in the secretory granules of mast cells. Upon stimulation, it is released in its active form into the local tissue, contributing to the activation of TGF-ß, matrix metalloproteases and cytokines.

BI-1942 is a highly potent inhibitor of human chymase (IC50 = 0.4 nM) that can be used to test biological hypotheses involving this target in vitro. With BI-1829 we also offer a structurally close analog that is more than 1000 fold less active (IC50 = 850 nM) and can thus be used as negative control for in vitro studies.

BI-1942

ChemBridge Macrocycle Library

Macrocycles offer a unique opportunity to address some of the more challenging drug targets and I've highlighted this on a couple of pages on the Drug Discovery Resources, here and here.

Macrocycles lie outside the usual "drug space" delineated by the Rule-of-5 and macrocycles can adopt different conformation in various media, hiding polar atoms or forming intramolecular hydrogen bonds, thus retaining good cell permeability and ADME properties

bRo5macrocycles

I recently got an email from ChemBridge highlighting a new 11,000 member Macrocyclic Library for screening. The general characteristics of compounds in the ChemBridge Macrocycle Library include:

  • Molecular weight range up to 800
  • Primary ring size ranging from 11 to 27 atoms
  • Heterocyclic primary rings
  • Scaffolds with and without peptidic backbone elements as part of the macrocyclic ring
  • Scaffolds with and without fused rings as part of the primary macrocyclic ring

More concerns about target validation

As a consultant I perhaps see more instances than most of the problems of reproducing literature studies, and I've highlighted several articles that have raised concerns. In particular, the concerns about antibody selectivity, the problems with irreproducible studies and the need for well characterised chemical probes. The excellent work by Elisabeth Bik 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,

This latest correspondence in Nature highlights some of the issues, "Industry is more alarmed about reproducibility than academia" DOI.

This paragraph I find particularly troubling.

By contrast, academic scientists may be reluctant to devote extra time and effort to confirming research results in case they fail. That would put paid to publication in high-impact journals, damage career opportunities and curtail further funding. Evidence of questionable practices such as selective publishing and cherry-picking of data indicates that rigour is not always a high priority.

Drug Discovery Books

 

The post highlighting the RSC MedChem School reminded me that I occasionally get asked to suggest books on Drug Discovery. I've compiled a list of books here, if anyone has suggestions for additions please let me know.

2019 Medicinal Chemistry Residential School

Registration for the RSC 2019 Medicinal Chemistry Residential School is now open, it takes place in Loughborough, UK 2-7 June 2019.

Through an in-depth programme of lectures, case studies and hands-on tutorial sessions, this five-day course strengthens excellence in medicinal chemistry by advancing understanding of the factors governing modern drug discovery. Full details are here.

Amodiaquine

Make sure that you register for this course as soon as possible to take full advantage of early bird savings. Registration includes attendance at all sessions, refreshments and lunch on each full day – plus a conference dinner with wine on Thursday 6 June.

Neglected and Tropical Diseases

I've tried to support research in the Neglected Tropical Disease area in several ways, I organised a session at the 19th Cambridge MedChem Meeting in 2017 and arranged for the session to be recorded and is now available online and has been watched nearly 300 times.

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).

So I was delighted to hear that IUPHAR/BPS Guide to pharmacology database have been funded by MMV to add details of antimalarials to their database.

This link http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=970 gives details of antimalarial targets, including gene name, synonyms and Uniprot ID.

This link http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=999 gives details of antimalarial ligands, including mode of action and properties. For example artemisinin.

artemisinin

I'd urge you have a look and I'm sure they would be happy to hear any suggestions.

Drug Discovery Resources Updated

I've spent a little time updating the Drug Discovery Resources Section of the website. In particular:

halogenbindingcomparison

20th SCI/RSC Medicinal Chemistry Symposium

20th SCI/RSC Medicinal Chemistry Symposium on 8 - 11 September 2019 at Churchill College, Cambridge.

Abstract deadline: Friday 9th November 2018

The organising committee wishes to solicit late-breaking, high impact medicinal chemistry talks to finalise the scientific programme. Potential contributions should be communicated to the secretariat at conferences@soci.org by Friday 9th November 2018. A number of conference places will be reserved for poster presenters and contributions are invited from the whole field of medicinal chemistry. Those presenting a poster may also elect to advertise their poster via oral presentation of a single slide 'flash' poster. Detailed procedures and submission deadlines for poster abstracts will be provided in the second announcement.

More details

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Cyclophilin D as a drug target

Cyclophilin D (CYP D), is a member of a family of highly homologous peptidylprolyl cis-trans isomerases (PPIases) that interconvert the cis and trans isomers of peptide bonds with the amino acid proline. Proteins with prolyl isomerase activity include cyclophilins, FKBPs, and parvulin. Inhibitors of Cyclophilin D have been postulated as potential drugs for a variety of therapeutic targets including anti-viral activity DOI, neurodegenration DOI, Cancer DOI etc.

Until recently work in this area suffered from the lack of high quality, selective inhibitors, the best studied being the immunosuppressants Cyclosporin and Sanglifehrin A.

CsA_SanglifehrinA

At the recent Macrocycles 2018 meeting Vicky Steadman described the identification and optimisation of potent and orally available selective Cyclophilin inhibitors, more details have just been published J Med Chem paper DOI.

Cyclod

Let's hope with potent, cell penetrant and orally available tools in hand we can sort out the biology and bring forward a new class of therapeutic agents.