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Cambridge MedChem Consulting

Ten threats to global health in 2019

A recent publication by the World Health Organisation makes sobering reading.

The world is facing multiple health challenges. These range from outbreaks of vaccine-preventable diseases like measles and diphtheria, increasing reports of drug-resistant pathogens, growing rates of obesity and physical inactivity to the health impacts of environmental pollution and climate change and multiple humanitarian crises.

Here are 10 of the many issues that will demand attention from WHO and health partners in 2019.

  • Air pollution and climate change
  • Noncommunicable diseases (diabetes, cancer and heart disease)
  • Global influenza pandemic
  • Fragile and vulnerable settings (combination of drought, famine, conflict, and population displacement)
  • Antimicrobial resistance
  • Ebola and other high-threat pathogens
  • Weak primary health care
  • Vaccine hesitancy (the reluctance or refusal to vaccinate despite the availability of vaccine)
  • Dengue
  • HIV

Medicines for Malaria Venture call for proposals

MMV has announced a call for drug discovery proposals

1. Compounds addressing the key priorities of the malaria eradication agenda

Novel families of molecules in the hit-to-lead or lead optimization stages are sought without G6PD deficiency liabilities that either:

Kill or reactivate hypnozoites for use as part of a P. vivax radical cure; or have activity against sexual stage V gametocytes and evidence of transmission blocking in SMFA.

2. Compounds having activity against asexual liver and/or blood stages

Novel chemical series with EC50<500nM and which have one or more of the following key features:

A known, novel mechanism of action; An inability to select resistant mutants in vitro; Activity at more than one life-cycle stage; A long half-life (ideally >4h in rodents) and confirmed in vivo efficacy. For advanced series, we are seeking novel compounds with, ideally, a predicted human half-life >100h and a predicted oral single human dose <500mg or an i.m. dose that can be administered in <1mL and sufficient for up to 3 months’ protection in humans.

3. Novel approaches for screening

To help identify new phenotypic and/ or target based hits, as well as confirm activity of MMV compounds on all human malaria asexual blood stages, new screening proposals are sought amongst the three categories below:

Validated Plasmodium target-based assays, ideally with evidence of target essentiality beyond asexual blood stages. Biological validation should be supported by a biological target based screening assay suited for identification of novel chemical series. Novel whole cell phenotypic screening paradigms to potentially identify new relevant chemistry. Asexual blood stage assays for vivax and ovale malaria.

Compounds for Target Identification

MMV also welcomes requests for support to investigate the mechanism of action of compounds:

Call for African proposals

Finally, MMV welcomes proposals from endemic region African scientists focused in the following priority areas:

  1. Compounds with confirmed activity on any antimalarial life-cycle stage. Novel families of molecules with confirmed activity (EC50 < 10uM) and a medicinal chemistry plan that tackles any known or anticipated liability. Priority will be given to proposals that maximize use of local natural products.

  2. Assay development and screening

Interesting meetings

In many companies/institutions/universities new arrivals are presented with a variety of desktop tools with little or no advice on how to use them other than "pick it up as you along". This workshop is intended to provide expert tutorials to get you started and show what can be achieved with the software.

The tutorials will be given a series of outstanding experts Christian Lemmen (BioSolveIT), Akos Tarcsay (ChemAxon), Giovanna Tedesco (Cresset), Dan Ormsby (Dotmatics) Greg Landrum (Knime ) and Matt Segall (Optibrium), you will be able to install the software packages on you own laptops together with a license to allow you to use it for a limited period after the event.

Registration opened just before Christmas and apparently there were a number of people sign up over the festive period. Remember there are a limited number of places and it is first come first served.

Registration and full details are here.

Computational Tools Flyer

Also a free one-day symposium Streamlining Drug Discovery" in Frankfurt
The very successful symposia series "Streamlining Drug Discovery" comes to Frankfurt on 14 February 2019. Jointly BioSolveIT, Optibrium, Lhasa and Elsevier invite you for this free one-day event highlighting new approaches and technologies being applied to the search for future therapeutics. For further details please visit the symposium website https://www.biosolveit.de/symposium/2019-02-14/



How Structural Biologists and the Protein Data Bank Contributed to Recent FDA New Drug Approvals

An interesting review DOI

Discovery and development of 210 new molecular entities (NMEs; new drugs) approved by the US Food and Drug Administration 2010–2016 was facilitated by 3D structural information generated by structural biologists worldwide and distributed on an open-access basis by the PDB. The molecular targets for 94% of these NMEs are known. The PDB archive contains 5,914 structures containing one of the known targets and/or a new drug, providing structural coverage for 88% of the recently approved NMEs across all therapeutic areas. More than half of the 5,914 structures were published and made available by the PDB at no charge, with no restrictions on usage >10 years before drug approval. Citation analyses revealed that these 5,914 PDB structures significantly affected the very large body of publicly funded research reported in publications on the NME targets that motivated biopharmaceutical company investment in discovery and development programs that produced the NMEs.

Annual Website Review

As 2019 starts I'd like to wish you all a Happy New Year and hope for great success in your drug discovery endeavours.

The Drug Discovery Resources website continues to increase in popularity with over 147,000 page views, an increase of 8% over the figure for 2017. The pages were visited by over 72,500 viewers and around a third of the visitors come back on multiple occasions suggesting they find it useful. The visitors come from 172 different countries with the US (32%), UK (13%) and India (8%) topping the list.

The most viewed pages in 2018 were

There have been a number of significant updates to the Drug Discovery Resources this year, in particular, a new section on Macrocycles which has proved very popular. The Target Validation section has been updated several times, as has the Molecular Interactions page and I'm grateful for readers who have pointed out relevant recent publications.

cypbindingsite.png

Interestingly the Books and Grant funding research have seasonal peaks in viewing.

Looking at the operating systems 56% are Windows users, 20% Mac users, 10% iOS and 10% Android, Chrome dominates the browser stats (64%) with Safari second (17%) and Firefox third (10%).

Open Targets Platform Updated

The latest update to the Open Targets Platform has been released (18.12).

Centre for Therapeutic Target Validation is a pre competitive public-private venture that aims to provide evidence on the biological validity of therapeutic targets and provide an initial assessment of the likely effectiveness of pharmacological intervention on these targets, using genome-scale experiments and analysis. The platform currently contains 28,931 targets, 3,049,882 associations for 10,053 diseases.

There is an open access portal to the platform here https://www.targetvalidation.org. All data is also available for download https://www.targetvalidation.org/downloads/data.

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.