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Cambridge MedChem Consulting

Covalent Inhibitors

I've just added a page on irreversible covalent inhibitors, this is just the first iteration I plan to add more when I have some spare time.

hcv

Selecting hits from virtual screening

Whilst high-throughput screening (HTS) has been the starting point for many successful drug discovery programs the cost of screening, the accessibility of a large diverse sample collection, or throughput of the primary assay may preclude HTS as a starting point and identification of a smaller selection of compounds with a higher probability of being a hit may be desired. Directed or Virtual screening is a computational technique used in drug discovery research designed to identify potential hits for evaluation in primary assays. It involves the rapid in silico assessment of large libraries of chemical structures in order to identify those structures that most likely to be active against a drug target. The key question is then how many molecules do you select from your virtual screen?

The results of a virtual screening run are effectively a rank ordering of the virtual screening deck ordered by whatever scoring function(s) that have been used. The task then becomes selection of molecules for experimental determination of activity.

I posed this question on the website and the results are shown below. Whilst this obviously a limited snapshot it is interesting that there is a wide variety of responses.

screening

I've included the results on the page on Selecting Compounds from a Virtual Screening Run.

Measles eliminated in 33 countries

WHO Europe is reporting the elimination of measles or rubella can be verified once a country has sustained interruption of endemic transmission for at least 36 months. The RVC verified that the following countries achieved elimination status as of 2016 for one or both diseases *:

  • Denmark, Spain and the United Kingdom eliminated measles;
  • The Republic of Moldova, Sweden and the former Yugoslav Republic of Macedonia eliminated rubella;
  • Croatia, Greece, Iceland, Lithuania, Montenegro and Uzbekistan eliminated both measles and rubella.
  • Spain and United Kingdom achieved elimination status for rubella as of 2015

This is another great success for the vaccination program with Measles no longer endemic in 79% of the WHO European Region

Full details here http://www.euro.who.int/en/media-centre/sections/press-releases/2017/measles-no-longer-endemic-in-79-of-the-who-european-region

Multidisciplinary Project Award

I'm delighted to hear that CRUK and EPSRC are funding a scheme to encourage research collaborations between different disciplines.

Multidisciplinary Project Award supports collaborations between cancer researchers and scientists from engineering/physical science disciplines.

Applications should ideally include:

  • a minimum of two PIs working in distinct scientific disciplines
  • at least one PI working in cancer research at any career stage
  • at least one PI from an engineering/physical science discipline at any career stage

Applications will be accepted from UK universities, research institutions, Cancer Research UK core-funded Institutes, medical schools and hospitals. The award is not required to be co-located and can be held across institutions in the UK, supporting roles from international and commercial organisations may also be included.

The Medici Effect, With a New Preface and Discussion Guide: What Elephants and Epidemics Can Teach Us About Innovation

The book is the basis for "The Medici Effect," a term coined by Johansson and used throughout various industries to describe innovation that happens when disciplines and ideas intersect.

This might go some way towards correcting the bias against interdisciplinary research

Causes of death over 100 years

The UK Office of National Statistics has produced a fascinating interactive plot of the causes of death in the UK over the last 100 years.

I've captured a screenshot of the plots but I'd urge to go and have a look at the interactive plot on the website http://visual.ons.gov.uk/causes-of-death-over-100-years/.

deaths

What is very apparent is the impact the introduction of antibiotics had in the late 1940's, and the introduction of mass vaccinations, deaths due to infections have been virtually eliminated.

In men heart disease remains the major killer whilst in women it is breast cancer. Sadly among the young it looks like mental health issues are a major concern.

Capps Green Zomaya Award

Nominations close on 31 October 2017

This Award was founded in 2002 in memory of the chemists Nigel Capps, Richard Green and Alex Zomaya to recognise outstanding contributions to medicinal or computational medicinal chemistry.

  • Run biennially
  • The winner receives £2000, a certificate and a medal
  • The winner is invited to give the 'Capps Green Zomaya Memorial Lecture' at the East of England
  • Medicinal Chemistry Symposium in April 2018
  • The winner will be chosen by an independent panel of senior chemists, selected by the Committee of the RSC Biological and Medicinal Chemistry Sector (BMCS) and the Capps Green Zomaya Trust.

More details are here http://www.rsc.org/ScienceAndTechnology/Awards/CappsGreenZoyama/

How many compounds do you select from virtual screening?

Whilst high-throughput screening (HTS) has been the starting point for many successful drug discovery programs the cost of screening, the accessibility of a large diverse sample collection, or throughput of the primary assay may preclude HTS as a starting point and identification of a smaller selection of compounds with a higher probability of being a hit may be desired. Directed or Virtual screening is a computational technique used in drug discovery research designed to identify potential hits for evaluation in primary assays. It involves the rapid in silico assessment of large libraries of chemical structures in order to identify those structures that most likely to be active against a drug target. The key question is then how many molecules do you select from your virtual screen?

Whilst virtual screening is certainly less expensive than high-throughput screening it is not free, even an in house academic cluster has an overhead (probably equating to > $10,000 per virtual screen). So with that investment how much would you invest in actual compounds?





19th Cambridge MedChem Meeting

The 19th RSC / SCI Medicinal Chemistry Symposium (#19thCamMedChem) takes place 10th-13th September 2017 at Churchill College, Cambridge, UK. This biennial meeting is one of the highlights of the drug discover calendar. Each meeting we try to enhance the scientific programme and this time there will be a live webcast of one of the sessions.

flyer

New for 2017 - Live Webcast Session on Neglected Tropical Diseases
Tuesday, 12th September Afternoon (13-30pm start).
Session Chair: Chris Swain, Consultant, UK

Introduction to the Neglected Tropical Diseases (NTD) session
Kelly Chibale, University of Capetown, South Africa
PI4K inhibitors that target multiple life cycle stages of the human malaria parasite
Kelly Chibale, University of Capetown, South Africa
Discovery and characterization of ACT-451840: an antimalarial drug with a novel mechanism of action
Christoph Boss, Actelion, Switzerland

Refreshments and short film clips

Rapid discovery of non-covalent inhibitors of DprE1, a novel and exciting target to treat Mycobacterium tuberculosis: impact of medicinal chemistry on an open source collaboration
Rob Young, GlaxoSmithKline, UK
Potent, selective and orally efficacious inhibitors of Plasmodium falciparum Protein Kinase G (PfPKG)
Jon Large, LifeArc, UK
First disclosure of a new oral development candidate for the treatment of visceral and cutaneous leishmaniasis
Charlie Mowbray, DNDi (Drugs for Neglected Diseases initiative), Switzerland
Closing remarks for NTD session
Charlie Mowbray, DNDi, Switzerland

The meeting is now fully booked but we hope that scientists around the world will be able to watch the presentations live using this link

LiveStream.

Please feel free to share this link.




Trust but verify

There is an article in Nature describing a collection of problems that have arisen from incorrect chemical structures in biological screens DOI. I'm slightly surprised that this is regarded as newsworthy, but I guess it serves as a timely reminder.

The data from screening campaigns invariably contains errors

  • It is often a single point assay
  • Quality and diversity of Sample Collection is variable
  • Compounds may interfere with the detection system
  • False positives due to aggregation
  • High density plates can result in cross contamination, edge effects

There is a very simple mantra you should adopt when analysing screening data "Trust but verify".

  • Check compounds that were found active against the selected target are re-tested using the same assay conditions used during the HTS.
  • Does a resynthesised (not repurchased) show the same activity
  • Dose response curve generation: an IC50 or EC50 value is then generated, does it have a reasonable slope? Uneffected by incubation time.
  • Are related analogues available, check for genuine Structure-Activity Relationships

elf

There is a strategy for the analysis of HTS data in the Drug Discovery Resources.

Molecules of Murder

I see that John Emsley, author of the new book Molecules of Murder: Potential Poisons is at a book signing tonight https://twitter.com/RoySocChem/status/901054073440526340

DIEv50lVYAAmPOM

If you can't make it, the books are available elsewhere. The ideal coffee table book.