I'm giving some talks over the summer, and am getting bored with some of the stuff I have, so I'm thinking of some new stuff to put in to add a bit of variety and interest. I'm getting interested in thinking about assay level attrition, and trying to put more of a taxonomy and inter-relationship mapping between assays used in drug discovery. As part of this, there is a cost component for each type of assay, going from very cheap to really really expensive. Here's a little picture from the presentation I've put together - I used educated guesses for the costs, so please, please critique them !
So, what do people think of the guesstimates of costs per compound per assay point on the picture above. I know it is really variable, there are startup costs to set something up, etc, etc. But what do you think about the orders of magnitude, are they about right? One of the key features of the numbers I've put there, are that there are big transitions at the switch between in silico and in vitro, and then on entering clinical trials.
An early heads up to a seminar from Andy Bell (now at Imperial College) to be held here on campus, detailing the discovery and development of UK-92,480 (also known as sildenafil and even better known as V1agra and R3vat10). Andy was one of the medicinal chemists and inventors on the PDE-5 inhibitor programme at Pfizer, and the story covers many aspects of drug discovery including, of course, the discovery of the side effect, and also one where the pharmacology led to many new molecular insights into NO signalling and PDE biology.
There are many myths about the discovery of V1agra, so this is a rare opportunity to hear the exciting story first-hand.
The seminar is on Tuesday July 17th2012 at 2pm in room C209 - you will need to mail me in order to get registered with campus security if you don't work on campus. If you do, you can just turn up.
The presentation will not be webcast, or recorded, or posted on Youtube (sorry).
Paul Workman of the Institute of Cancer Research is due to feature in a BBC Radio 4 special exploring the future of drug discovery in the UK, which will be broadcast tomorrow Tuesday 22nd May. The 40-minute programme, called The End of Drug Discovery and presented by veteran science broadcaster Geoff Watts, starts at 8pm.
The programme will “examine whether sources of better pharmaceutical treatments are drying up, in light of reports that suggest making new and improved drugs available to patients is becoming more difficult and increasingly expensive,” the BBC said. Professor Workman was recorded discussing the issues facing the pharmaceutical industry, and the role that non-profit and academic organisations like the ICR can play in driving drug discovery progress.
There will come a point in time when a new GPCR structure doesn't 'make the grade' for Nature or Science, but hopefully that time is still a considerable way off. There are two new GPCR structures released recently - the nociceptin receptor 4ea3 and the delta-opioid receptor 4ej4, bringing it to a grand total of 15 sequence distinct rhodopsin-like GPCR structures in the public domain.
Both new ones published alongside two other previously released PDB entries in last weeks Nature.
Here is an alignment - thanks to the commenter on a previous post in this series that spotted my schoolboy error in a previous version.
%T Crystal structure of the µ-opioid receptor bound to a morphinan antagonist
%A A. Manglik
%A A.C. Kruse
%A T.S. Kobilka
%A F.S. Thian
%A J.M. Mathiesen
%A R.K. Sunahara
%A L. Pardo
%A W.I. Weis
%A B.K. Kobilka
%A S. Granier
%J Nature
%V 485
%P 321–326
%O doi:10.1038/nature10954
%D 2012
%T Structure of the human κ-opioid receptor in complex with JDTic
%A H. Wu
%A D. Wacker
%A M. Mileni
%A V. Katritch
%A G.W. Han
%A E. Vardy
%A W. Liu
%A A.A. Thompson
%A X.-P. Huang
%A F.I. Carroll
%A S.W. Mascarella
%A R.B. Westkaemper
%A P.D. Mosier
%A B.L. Roth
%A V. Cherezov
%A R.C. Stevens
%J Nature
%V 485
%P 327–332
%O doi:10.1038/nature10939
%D 2012
%T Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic
%A A.A. Thompson
%A W. Liu,
%A E. Chun
%A V. Katritch
%A H. Wu
%A E. Vardy
%A X.-P. Huang
%A C. Trapella
%A R. Guerrini
%A G. Calo
%A B.L. Roth
%A V. Cherezov
%A R.C. Stevens
%J Nature
%V 485
%P 395–399
%O doi:10.1038/nature11085
%D 2012
%T Structure of the δ-opioid receptor bound to naltrindole
%A S. Granier
%A A. Manglik
%A A.C. Kruse
%A T.S. Kobilka
%A F.S. Thian
%A W.I. Weis
%A B.K. Kobilka
%J Nature
%V 485
%P 400–404
%O doi:10.1038/nature11111
%D 2012
There was a lovely paper in Nature Medicine recently by James McKerrow and colleagues from UCSF on the discovery that auranofin is a good anti-amoeba agent. As the name suggests, auranofin contains gold, and would not make many people's lists of drug like compounds, but hey it's a drug, a real drug!
Anyway, it got me thinking a bit about drug reuse, and the current drug development process is probably configured to make drug repurposing/indication expansion/rescue/whatever a sweet spot for academics, with relatively few incentives for pharma and biotech to actively pursue. I'm sure others have thought of this before, so sorry for being repetitive. I think biologicals will be a different kettle of fish.
Current patent life is too short to allow cautious post-approval studies in new indications in most cases, especially for diseases that are chronic and have a long read-out. What are the incentives for a company to perform these trials, when they are in reality probably getting a small bump on revenue at the tail end of the patent life, and building a market for generics. As an aside, I am coming firmly to the view that the patent system for drugs is just wrong. To base the system on reward for 21st Century R&D in healthcare on the length of medieval apprenticeships is just plain mad (see here for a little pointer to background).
Regulators are (quite rightly) cautious, and extra hurdles of cost-effectiveness and price negotiations again don't work towards the developing company for a drug actively pursuing new indications - there was a recent case for Aricept, where a recent study recommended use at an earlier stage of Alzheimer's, following many years of regulators turning down data from the developer's encouraging earlier use on the basis of their data. If it is the case that Aricept is helpful to patients with milder disease, for this to happen when the drug becomes generic is a bitter pill (no pun intended). I will check the facts on this and then update if it is way off.
Taken further - isn't one strategy for health providers with an eye on costs to resist new indications precisely until the drug is generic. Of course, this allows the building of a good safety record for the drug, across a far more diverse and ill patient population.
Academics (pre-clin and clinical) (and of course non-profits) have different drivers with respect to reward, and there is a pretty good alignment between the 'business model' of academic and drug repositioning studies maybe. However, other factors may kick in here, lack of funding, risk aversion, lack of experience and naivety of the process, and there are also sharp contrasts between the personality free operations of pharma (usually) and the personality rich environment of academia (usually).
Release of data from the initial compound developers is obviously a good thing - many pairs of eyes looking at the data, preventing wasted effort, etc. but what are the drivers for release of such data? It is expensive to do, and would be seen by some (investors and staff) as throwing money away.
This is a last call for people wanting to sign up for the "Schema & SQL Querying" webinar that will be hosted this Wednesday 16th May at 3.30pm (BST).
It will be a 45 minute webinar that will take you through the ChEMBL schema and also how to use SQL queries to extract data from the database.
Remember to register your interest in our webinars on the Doodle Poll. Make sure that you leave your **email address** as well as your name so that we can send the connection details to you. Any problems, please contact chembl-help@ebi.ac.uk.
For those of you who can't make it to this webinar, we will be hosting it again on the 27th June.
On May 1, the FDA approved taliglucerase alfa for the treatment of Type I Gaucher's disease. Gaucher's disease is the most common of the lysosomal storage diseases. It is a hereditary disease caused by a deficiency of the enzyme β-glucocerebrosidase (Uniprot: P04062), also called β-Glucosidase. Gaucher's disease is a rare genetic disease with an incidence of 1 in 50,000 births and is considered an orphan disease. Type I Gaucher's disease is about 100 times more common in people of Ashkenazi jewish descent compared a north American population. Symptoms of type I Gaucher's disease begin typically in early adulthood and include enlarged liver and grossly enlarged spleen, impaired bone structure, anemia and low platelet levels, leading to prolonged bleeding and easy bruising. If enzyme replacement therapy (ERT) is available, the prognosis for patients with type I Gaucher's disease is good.
β-Glucocerebrosidase is an enzyme of 536 amino acids and molecular weight of approximately 59.7 kDa. The gene for β-glucocerebrosidase is located on the first chromosome (1q21) and catalyzes the hydrolyzation of glucocerebrosides (eg. ChEBI:18368), a process required for the turnover of the cellular membranes of red and white blood cells. Macrophages clearing these cells fail to metabolize the lipids, accumulating them instead in their lysosomes. Thus, macrophages turn into dysfunctional Gaucher cells and abnormally secrete inflammatory signals. The deficiency of glucocerebrosidase in Type I Gaucher's disease is only partial and in most cases caused by a mutation replacing asparagine with serine in the 370th residue of the protein sequence. The deficiency of the mutant enzyme can be compensated by injection of an exogenous replacement and drastically improve the prognosis for patients with type I Gaucher disease. Prior to the approval of taliglucerase alfa, imiglucerase and velaglucerase alfa were already available ERTs for type I Gaucher's disease. The graphic below illustrates the reaction catalyzed by β-glucocerebrosidase and ERTs. The enzyme classification code for β-glucocerebrosidase is 3.2.1.45.
Taliglucerase alfa is a monomeric glycoprotein containing 4 N- linked glycosylation sites and has a molecular weight of 60,8 kDa. The recombinant enzyme differs from native human glucocerebrosidase by two amino acids at the N terminal and up to 7 amino acids at the C terminal. Taliglucerase alfa is decorated with mannose-terminated oligosaccharide chains that are specifically recognized by macrophage receptors and assist in 'homing' the enzyme to its target cells.
Taliglucerase alfa is the first ERT expressed in plant cells (carrot root cells), not mammalian cells. Cultures of plant cells are more cost-effective for the expression of recombinant enzymes.
Crystal structure of the human glucocerebrosidase (PDBe 1ogs).
The recommended dose is 60 Units/kg of body weight administered once every 2 weeks as a 60-120 minute intravenous infusion. A Unit is the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. Adverse effects include pharyngitis, headache, arthralgia, flu and back pain.
Taliglucerase alfa is marketed by Pfizer and Protalix under the brand name Elelyso. The full prescribing information can be found here.
