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Paracetamol Challenge

Sadly it appears that the latest craze to sweep social media is the Paracetamol Challenge in which people (usually children) are encouraged to consume large amounts of the over the counter analgesic paracetamol (called acetaminophen in North America).

One of the particularly insidious features of paracetamol toxicity is that individuals may display little or no symptoms in the first 24h, it is only later when increasing liver damage has occurred do the more serious symptoms become apparent.

What is the mechanism of Paracetamol Toxicity

At normal therapeutic doses paracetamol the main route for clearance is by Phase II processes including conjugation to form the glucuronide or sulphate followed by renal clearance. At higher doses however, paracetamol is oxidised by CYP450 enzymes in the liver to a highly reactive intermediary metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI can be detoxified by conjugation with glutathione (GSH) to form cysteine and mercapturic acid conjugates however this pathway has limited capacity and once supplies of glutathione are exhausted if NAPQI remains it can react covalently with biomolecules resulting in widespread hepatocyte damage and death, leading to acute hepatic necrosis. Without treatment this progresses to irreversible liver, kidney failure followed by multiple organ failures.

actaminophen

Treatment

If caught within an hour of ingestion gastric lavage may be used to remove any drug that has not yet been absorbed, at later stages N-acetylcysteine can be administered. This works to reduce paracetamol toxicity by replenishing body stores of glutathione (GSH). However N-acetylcysteine needs to be administered before liver damage has occurred, if given more than 8 hours after ingestion of paracetamol it's effectiveness is reduced. If patients develop hepatic failure or who are otherwise expected to die from liver failure, the mainstay of treatment is liver transplantation.

Lack of reproducibility with antibodies

A slightly worrying article in Nature, Reproducibility crisis: Blame it on the antibodies.

The lack of reproducibility of published data on potential drug targets has been highlighted on several occasions DOI and it has been suggested that this is a major factor in the failure rate for phase 2 clinical trials DOI.

In almost two-thirds of the projects, there were inconsistencies between published data and in-house data that either considerably prolonged the duration of the target validation process or, in most cases, resulted in termination of the projects.

Antibodies have rapidly become a key tool in understanding and identifying new drug targets and potentially used as biomarkers to identify patients. However it is clear that many of the 2 million commercially available antibodies need to be checked rigorously, with some scientists claiming more than half are unreliable.

In 2011, an evaluation4 of 246 antibodies used in epigenetic studies found that one-quarter failed tests for specificity, meaning that they often bound to more than one target. Four antibodies were perfectly specific — but to the wrong target.

Caveat emptor.

Medicinal Chemistry Toolkit app

A review of the Medicinal Chemistry Toolkit app for iOS

http://www.macinchem.org/reviews/mctk/medchemtoolkit.php

The role of solvent in ligand binding

The role of water in ligand binding is often ignored and I thought it might be useful to add information to the drug discovery resources section. In particular :-

Expanding the page on molecular interactions

and adding a page on Solvation and Desolvation

If you have time to have a look, any comments or suggestions would be very welcome.


The OpenFDA Developer Challenge

The FDA is launching its very first openFDA challenge to the developer community to take advantage of the following datasets and explore the range and extent of its impact for 1) research and 2) consumers.

  • Adverse events data. FDA’s publicly available drug adverse event and medication error reports, and medical device adverse event reports.

  • Recalls data. Enforcement report data, containing information gathered from public notices about certain recalls of FDA-regulated products.

  • Labeling data. Structured Product Labeling (SPL) data for FDA-regulated human prescription drug, OTC drug and biological product labeling.

How to Participate

Choose the challenge and option you’re most interested in, from above.

Tweet @openFDA with the challenge you’ll be working on, using #openFDAchallenge. To level up your competition, invite your friends.

Start working on a solution to the challenge either by flying solo or with a team.

When you’ve got something to show, submit a link to your project on the openFDA subreddit, and vote or comment on your favorites. That’s it!

Remember: You can always post questions to StackExchange about the challenge or the data, using the tag: openFDA


European Lead Factory

The European Lead Factory has just announced that an additional 50,000 new compounds have been added to their screening collection. This brings the collection up to 350,000 compounds and sets them well on the way to their 500,000 target.

I've been involved in a couple of projects that have made use of this high-throughput screening facility and I've been impressed with the quality and diversity of the hits generated.

The European Lead Factory was established to promote the discovery of novel lead compounds, suitable for subsequent optimization either to drug candidates or to high‐quality pharmacological tools for the experimental validation of targets.

If you have a target you want to screen against you can submit a proposal online. For an academic or small company this is an interesting way to identify novel starting points for a medicinal chemistry program.




Wellcome Trust Seeding Drug Discovery Program

I just got sent an email reminding me about the deadline for submissions for applications to the Wellcome Trust Seeding Drug Discovery Program.

Funding to facilitate early-stage small-molecule drug discovery. The awards help applicants with a potential drug target or new chemistry embark on a programme of compound discovery and/or take later stage projects towards clinical trials.

The next deadline for the preliminary application is 5 June 2015.

I've been involved in several projects funded by this initiative and it seems an excellent scheme.

If you are thinking about grant funding your research there are a number of other opportunities.

RSC Medicinal Chemistry Residential School

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There is less than a week left to save £50 with early bird registration for the RSC Medicinal Chemistry Residential School (21-26 June 2015, Burleigh Court Conference Centre, Loughborough University, UK).

The school is designed for graduate and post-doctoral chemists with 1-5 years' experience in the field of drug research. Drug discovery is an interdisciplinary subject so delegates from biological or computational backgrounds will benefit from attendance at the school. In addition, final year PhD students from pharmaceutical or organic chemistry contemplating a career in drug discovery are also encouraged to attend.

Full details here

Mitigating risk in academic preclinical drug discovery

An interesting paper in Nature Reviews Drug Discovery for those involved in academic drug discovery.

Mitigating risk in academic preclinical drug discovery, Jayme L. Dahlin, James Inglese & Michael A. Walters DOI

Here, we have outlined some risk mitigation strategies that can help set the stage for effective engagement at the academic–applied science interface. However, even with the best risk management, >95% of these projects will fail

The last point is particularly important for PhD student supervisors to note.

Hatfield MedChem Meeting

26th symposium on Medicinal Chemistry in Eastern England (Hatfield symposium)

Thursday, 23rd April 2015 The Fielder Centre, Hatfield, Herts, UK

Speakers and Presentations Identification of orally bioavailable type 2 inhibitors of discoidin domain-containing receptor 1/2 (DDR1/DDR2) using “back-to-front” X-ray FBDD Emiliano Tamanini, Astex Therapeutics

Drug discovery towards the eradication of malaria Paul Willis, Medicines for Malaria Venture

Exploring water networks to predict binding affinity and selectivity Daniel D Robinson, Schrödinger

URAT-1 solute carrier inhibitor program for the treatment of gout Ian Storer, Pfizer

The discovery of potent brain penetrant BACE inhibitors Fionna Martin, Lilly

The monster mas agonist – revealing the beauty in the beast Simon Peace, GlaxoSmithKline

The discovery of therapeutics for neglected diseases and the translation of novel biology through small molecule drug discovery Andrew Woodland, Drug Discovery Unit, University of Dundee

A softdrug approach to PDE4 inhibitors for the topical treatment of skin diseases Nuria Aguilar, Almirall

The European Lead Factory: a pan-European approach to access new chemical space for drug discovery Adam Nelson, University of Leeds

Novel 5-HT7 antagonists, with an unprecedented selectivity profile, for the treatment of migraine Ali Ates, UCB

Sulfoximine substituted morpholino-pyrimidines for the treatment of cancer Kevin Foote, AstraZeneca

Event website www.maggichurchouseevents.co.uk/bmcs