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Cambridge MedChem Consulting

Open Source Malaria Project

The Open Source Malaria team have submitted an entry for the Thinkable Open Innovation competition

Here it is: https://www.thinkable.org/submission/2055 Please go and watch the video and vote for the team.

The prize is $5000 and every dollar of the prize would go to supporting malaria research in OSM.

So please go to https://www.thinkable.org/submission/2055, sign up to Thinkable (very quick and easy - you can sign in through Facebook etc if you like) and vote for the project and tell your friends.

Putting a spotlight on University Technology Transfer

If you are an academic involved in drug discovery there is a paper in Nature Biotechnology that you should read that tells you what you need to know about your technology transfer office (TTO) doi.

The administrative complexity and opacity in university technology transfer presents an extra obstacle to academic entrepreneurs who already face a multitude of technical and commercial hurdles before their discovery can reach the marketplace. The best way to overcome these issues is to be fully informed before initiating negotiations with your TTO. We hope the information in this article will better prepare you to meet these challenges.

The article gives information on how long the negotiations can take with the TTO (up to 18 months!), and what you can do to improve the process. There is also the issue of the size of the stake the university will claim in the fledgling company

Perhaps the most striking difference between the United States and United Kingdom is seen with equity deal terms. In the United Kingdom, a typical licensing deal is a rarely negotiable 50:50 split between the university and the academic bioentrepreneur, whereas US interviewees often reported universities taking a 5–10% negotiable equity share.

The authors have tried to gather together the IP policies of the major universities in the US and UK and tabulated the equity share taken, some universities take 5% whilst others take over 67%. It should also be noted that in addition to the initial equity stake there might be long term milestone payments that need to be factored into the equation.

At a time when there is an effort to increase academic involvement in early stage drug discovery it is useful to have the spotlight shone on this often opaque area. Whilst this paper only reviews US and UK institutions I suspect similar issues exist in other countries.

Fragments in the clinic

The acid test for any new technology in drug discovery is whether it translates into drugs in the clinic. Practical Fragments have been keeping a track on candidates discovered using fragment-based screening and the 2015 update now contains over 30 drugs in various stages of clinical development. As someone who has seen a number of technologies come and go I'm delighted to see that fragment-based approaches are delivering where it counts.

There is more information on fragment-based screening in the Drug Discovery Resources.

18th SCI/RSC Medicinal Chemistry Symposium

The second flyer for the 18th SCI/RSC Medicinal Chemistry Symposium (Sunday 13 - Wednesday 16 September 2015 Churchill College, Cambridge , UK) is now available.

Again we have an outstanding international lineup with a special focus on challenging targets, "Drugging the undruggable".

The flyer including the application form can be downloaded from here.

Cambridge New Therapeutics Forum

I just got an email regarding a new set of meetings that may well be of interest.

A scientific forum open to all scientists interested in research and development of new therapeutics in Cambridge and the local area, including scientists at the University, Addenbrooke’s Hospital, pharmaceutical companies, biotechs, CROs, and not-for-profit organisations.

The purpose of Cambridge New Therapeutics Forum (CamNTF) is to promote interactions between scientists at these organisations in order to improve opportunities for biotechnology research and development.

Starting from 2015 CamNTF will host early-evening meetings open to all scientists interested in research into new therapeutics. These will rotate around different organisations located in the Cambridge biotech cluster. Each two-hour session will begin with two short scientific presentations and will be followed by networking and snacks (6pm-8pm).

Full details are available in the flyer

ADME pages updated

I've just updated the ADME section of the Drug Discovery Resources.

Any suggestions for additions very welcome.

Caveat emptor

A paper entitled Promiscuous 2-Aminothiazoles (PrATs): A Frequent Hitting Scaffold appeared in J Med Chem recently DOI, in which they describe the promiscuous nature of 2-aminothiazoles in screens.

Exemplified by 4-phenylthiazol-2-amine being identified as a hit in 14/14 screens against a diverse range of protein targets, suggesting that this scaffold is a poor starting point for fragment-based drug discovery

I thought I'd check how often this substructure appears in the published fragments database, indeed currently 43 of the 903 published fragments contain this substructure. Further investigation identifies a total of 63 amino-substituted 5-membered heterocycles, and there are 167 fragments in which there is an amino group on an aromatic ring (mainly heterocycles).

It should also be noted however that there are 64 structures in the DrugBank database that also contain a 2-aminothiazole, so whilst promiscuous they can be developed into drugs.

So whether they are privileged structures or troublesome promiscuous hits is probably in the eye of the beholder, caveat emptor.

Annual Site Review

At the end of each year I take the opportunity to look at the website analytics to see what parts of the website are the most popular. Overall there was a 15% increase in the number of page views up to 75,000. Average time on a page was 2 mins suggesting the content is engaging with the viewers.

Nine of the top ten most popular pages were from the Drug Discovery Resources Pages which I am delighted to see, since it suggests that the work entailed in putting the resources together is worthwhile.

The most viewed pages were

The most popular posts to the news/comments feed were

5th RSC-BMCS Fragment-based Drug Discovery meeting

Registration for the Fragments 2015 Meeting is open.

5th RSC-BMCS Fragment-based Drug Discovery meeting Sunday to Tuesday, 22nd to 24th March 2015 at Churchill College, Cambridge, UK

Always a very popular and informative meeting, the agenda is now finalised and looks excellent.

More on PAINS

I often get asked to help with the analysis of high-throughput screening results and one of the first filters I run as part of the hit identification is to flag for PAINS (Pan Assay Interference Compounds) first described by Baell et al DOI and subsequently summarised in an excellent Nature comment.

Academic researchers, drawn into drug discovery without appropriate guidance, are doing muddled science. When biologists identify a protein that contributes to disease, they hunt for chemical compounds that bind to the protein and affect its activity. A typical assay screens many thousands of chemicals. ‘Hits’ become tools for studying the disease, as well as starting points in the hunt for treatments.

These molecules — pan-assay interference compounds, or PAINS — have defined structures, covering several classes of compound. But biologists and inexperienced chemists rarely recognize them. Instead, such compounds are reported as having promising activity against a wide variety of proteins. Time and research money are consequently wasted in attempts to optimize the activity of these compounds. Chemists make multiple analogues of apparent hits hoping to improve the ‘fit’ between protein and compound. Meanwhile, true hits with real potential are neglected.

In the supplementary information they provided the corresponding filters in Sybyl Line Notation (SLN) format, however they have also been converted to SMARTS format and incorporated in sieve file for use in filtering compound collections. If you are a Vortex user then there is also a Vortex script available, filters are also available for Knime and now it is even available on mobile devices with MolPrime+.

It is probably not until you have been involved in multiple small molecule screens that you appreciate the number of ways that false positives can occur and just how much valuable time and resources can be wasted following them up. Indeed it may be for the more difficult targets the majority of hits seen may be false positives. Flagging PAINS is now such a well developed tool that it would be fool hardy not to include it.