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Cambridge MedChem Consulting

Setting up Cheminformatics Support for the Open Source Malaria Project

Here are the slides for a talk I gave at the Cambridge Cheminformatics Network Meeting in August.

Setting up Cheminformatics Support for the Open Source Malaria Project

Latest Publication

Bifunctional crosslinking ligands for transthyretin

P. Patrizia Mangione, Stéphanie Deroo, Stephan Ellmerich, Vittorio Bellotti, Simon Kolstoe, Stephen P. Wood, Carol V. Robinson, Martin D. Smith, Glenys A. Tennent, Robert J. Broadbridge, Claire E. Council, Joanne R. Thurston, Victoria A. Steadman, Antonio K. Vong, Christopher J. Swain, Mark B. Pepys, Graham W. Taylor

Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR–ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.


I've expended the preclinical toxicity section to include a page on hepatotoxicity. This gives some details of the common assays and markers used to evaluate the potential hepatotoxicity.

An Aggregation Advisor for Ligand Discovery

Aggregation is a regular concern when evaluating potential hits from screening and a recent paper "An Aggregation Advisor for Ligand Discovery" DOI attempts to provide an insight into this phenomenon, in addition they provide a useful web-based tool that provides a free service to advise whether molecules may aggregate under biological assay conditions.


Rare Diseases

There are between 5,000 and 8,000 rare diseases, and around 5 new rare diseases are described in the literature each week. There is no internationally recognised definition of a rare disease but they are defined by the European Union as one that affects less than 5 in 10,000 of the general population. Most rare diseases have a genetic component and if apparent in early life a significant number die before their 5th birthday. Reportedly only around 400 rare diseases have therapies and so I was interested to hear about The UK Strategy for Rare Diseases, if you have time it is an interesting read. The focus is more on the clinical side but the recognition of the need for robust epidemiological analysis and coordination of research activities of the major research funders is highlighted.

Useful sites:
Rare Diseases UK
National Organisation for Rare Diseases
Global Genes

EFMC Position Paper on Medicinal Chemistry

Changes in the Pharma industry have thrown into sharp focus the role of medicinal chemists, the European Federation for Medicinal Chemistry (EFMC) have now published a position paper defining the role of medicinal chemistry.

Medicinal chemistry is concerned with the design and synthesis of biologically active molecules. It aims at creating new chemical structures to better understand and influence physiological and/or pathological systems. Ultimately, it allows the discovery and optimization of novel drug candidates to address unmet medical needs, as exemplified by recent progress in the treatment of cancer, cardiovascular or infectious diseases.

You can read the full paper here.

Drug Discovery Resources Update

I spent the weekend updating the Drug Discovery Resources, in particular I added a page on Target Validation, updated the Hit Identification expanding the section on Published Fragment Hits, and updated the ADME section and Preclinical Checklist.

As ever any comments or suggestions are most welcome.

Acessing Open Source Malaria Data

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. To date a lot of people around the world have made contributions and the project is at a very exciting stage. Whilst everyone can see the compounds that have been made and the biological data, it is often spread over multiple web pages and can be tricky to link molecule with identifier with data. Over the last couple of months a significant effort has been put into populating a spreadsheet with all the information.

In addition to a Vortex script to access the information, there is now an iPython notebook that also shows how to import the data. Why not give it a try, do some analysis and build predictive models and then contribute your findings and suggestions to the Open Source Malaria project.


Time Dependent Inhibition

I've just updated the Drug Discovery Resources page on CYP Interactions, included a section on Time Dependent Inhibition (TDI).


An article on BuzzFeed suggests that Pharma companies are investigating the use of ResearchKit in clinical trial studies.

ResearchKit is an open source framework introduced by Apple that allows researchers and developers to create powerful apps for medical research. Easily create visual consent flows, real-time dynamic active tasks, and surveys using a variety of customizable modules that you can build upon and share with the community. And since ResearchKit works seamlessly with HealthKit, researchers can access even more relevant data for their studies — like daily step counts, calorie use, and heart rate

GlaxoSmithKline apparently is currently working on integrating (ResearchKit) into clinical trials and planning to start in coming months, whilst Purdue Pharma are in the early stages of exploring whether Apple’s new tool for research data collection can be used as part of its own drug R&D efforts.

So far, ResearchKit apps are being led by academic medical centers like the University of California, San Francisco, and nonprofits like Sage Bionetworks and the Michael J. Fox Foundation for Parkinson’s Research. LifeMap Solutions, a company that develops mobile health apps, helped create the asthma app in partnership with the Icahn School of Medicine at Mount Sinai. The first ResearchKit apps signed up more than 75,000 participants in just the first few months