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Paper: Mapping small molecule binding data to structural domains
We've just published a paper on mapping the sites of small molecule binding in complex multidomain proteins (pdf here - this link doesn't seem to work at the moment, sorry). The resolution of the mapping is at the level of Pfam domains. We love Pfam, and love it even more that the Pfam team is moving to the EBI this week. The motivation for this work is multifold, and it addresses a pretty big problem in chemogenomics.
Firstly the issue of domain frustration - you search a protein containing a series of distinct domains looking for homologues in ChEMBL. If your protein contains a common and uninteresting domain, something like a zinc finger or EGF domain (our interest is for small molecule binding remember, we're not saying that these domains are completely boring, they're just a lot less interesting from a chemical biology/drug discovery perspective) you'll retrieve a whole bunch of sequence related, but small molecule binding unrelated data. It's just the way bioinformatics works. You can be selective in searching with just the sequence of the domain you are interested in, but this only solves half the problem, since there's no guarantee that compounds retrieved will bind at that domain in the retrieved protein.
Secondly the issue of selective signalling - it is now common to see proteins as existing in pathways, and that there are key control nodes that are highly connected to many other proteins, a key question is therefore how signalling remains specific under this everything-is-linked-to-almost-everything-by-interactions setting. Well we think that the annotation of pathways at the domain interaction level is under-appreciated. For example, consider a protein X that interacts with three other proteins Y, W and Z, and that Y and Z interact through domain 1 in X, and W via domain 2. If you have a small molecule that binds to domain 1 in X, you will selectively affect downstream signalling to Z and Y only.
These data will end up in the next version of ChEMBL - but if you want to get hold of any data prior to this, check out the supplementary data for the paper.
Next steps? Well the approach to mapping and scoring the domains could be improved, and the resolution ideally needs to be at a site level within a domain - so that compounds that bind at different structural sites can be differentiated for model development, pharmacophores, etc. It is an undeniable fact that merging compounds that bind at different sites, with different binding determinants will not be able to predict each other. We have made some progress on this latter sub-problem, and more on that soon.
%T Mapping small molecule binding data to structural domains %A F.A. Kruger %A R. Rostom %A J.P. Overington %J BMC Bioinformatics %D 2012 %V 13 %O doi:10.1186/1471-2105-13-S17-S11
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The End Of The World As We Know It - Part 2
So, our cheap-skate super villain - Marcus Schtrukter - who's on a budget, as would fit these times of global austerity; could destabilise our chemical patent system in a simpler and far cheaper way. I mean, who has the money to spend on a secret lair nowadays? Even in developing economies labour isn't as cheap as it once was, the cost of cement is just sky-rocketing, the staff want iPhones, and they spend way too much time on twitter. Assembling a team of henchmen/women, is not easy - don't believe me? Just type "henchmen" into LinkedIn, and there's not a lot. The world is just full of social media mavens nowadays, unprepared to do evil, well any evil that involves getting their own hands dirty. Some numbers to back this up - for me, with my current LinkedIn network there's 112 henchmen and 2,935,294 social media people. Even if you recruited all of the skilled henchmen in the world, what sort of efficient lair could you run with only 112 staff.
So for this cheap version of world patent disruption - you just tell the world you've calculated GBD-46, have it on a large server farm somewhere, and that you're ready to check novelty of chemical structures as a service for the world. You just need a fancy building like the one above, some nice business cards, and an Internet presence, and an AWS account. It's just that you haven't really done any enumeration - remember, super-villains aren't like readers of the ChEMBL-og and would not worry about always telling the truth.
Your patent checking website, would just simply echo back the query (if it was chemically sensible), and say "yeah, that's in there, it's not novel". Now the smarter users would probably say "But how do I know it's in there?" It's pretty simple to rapidly enumerate a large set of compounds around a seed, using a simple rule set, just return these as nearest neighbours, and it looks like you really do have a database of every compound ever possible. To provide a veneer of credibility, you could offer the entire database for download, and of course the ftp site would just deliver an infinite stream of random numbers following a gzip header, for a download that either fills up the recipients disk, or never finishes.
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The End Of The World As We Know It - Part 1
The latest release of the fabulous GDB databases is out - GDB-17. Well it's almost out, a diverse 50,000,000 subset is available for download, not the full 166,000,000,000 compounds detailed in the paper. Which is a shame. I had a glass of port at lunch, with my (tinned) lobster bisque soup, and slipped off to sleep for a few minutes with some junk on the radio about the new James Bond film on in the background...... as is the case when you've on-board some crustacean, alcohol and combine it with some autosuggestion; I had a funny dream.
There was an evil super villain - Hugh Jin-chi, who had built a large compute farm buried deep in a mountain on a sub-tropical island, with associated nuclear power plants for cooling. It had one sole purpose, to enumerate every possible Lipinski-like small molecule and dump everyone of them in a publicly searchable free chemical database called ChemShadow, for use by patent agents the world over for novelty checking. His evil goal, to undermine the Western patent system for chemicals and destroy the very basis of healthcare research and patient benefits from pharmaceutical R&D. There was also something to do with 3D conformer generation, but that just seems crazy........
I woke up, sweaty, feverish and scared.
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USAN Watch: October 2012
The USANs for October 2012 have recently been published.
USAN Research Code Structure Drug Class Therapeutic class Target afoloxaner 
synthetic small molecule therapeutic
GSK-2110183C
synthetic small moleculetherapeuticAKTRDC-9003
synthetic small molecule prodrugtherapeuticD2, 5HT1A and othersRDC-3317 
synthetic small molecule prodrug therapeuticD2, 5HT1A and othersPMX-30063 
synthetic small molecule therapeuticn/aMEDI-573 monoclonal antibody therapeuticIGF, IGF-2TP-434046 
natural product derived small molecule therapeutic30S ribosomeP-449, Dotarem 
synthetic small molecule imaging agentn/aRO-4905417, LC-1004-002monoclonal antibody therapeuticP-selectinFEK-256-062
synthetic small molecule imaging agentNKTR-118 
natural product derived small molecule therapeuticopioid receptors
polymer contact lens materialn/aON-01210, ON-0120.Na, Ex-Rad 
synthetic small molecule radiation protection agent -
New Drug Approvals 2012 - Pt. XXII - Perampanel (FycompaTM)
ATC Code: N03AX22Wikipedia: Perampanel
On October 22nd 2012 the FDA approved Perampanel (research code: E2007, ER-155055-90, trade name Fycompa, CHEMBL1214124). Perampanel is an orally administered drug to be used as an adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalized seizures in patients with epilepsy.
Epileptic seizures are defined as "abnormal excessive or synchronous neuronal activity in the brain". The net symptoms can be very diverse, from severe thrashing movements to a very mild brief loss of awareness. Approximately 4% of the population will have experienced a unprovoked seizure by the age of 80, with a 30-50% chance of repeat in this group. Seizures can last from a few seconds to a state of life threatening persistent seizure (known as status epilepticus).
Approximately 25 % of the people suffering from a seizure or status epilepticus will be diagnosed to have epilepsy. Treatment may reduce the chance of a second seizure by as much as 50%.
Perampanel acts by non-competitively inhibiting the ionotropic α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) glutamate receptor. This receptor consists of a heteromeric combination of 2 out of 4 known subunits GluR-1 - GluR4 (respectively: CHEMBL2009, CHEMBL4016, CHEMBL3595 and CHEMBL3190 or Uniprot 42261, 42262, 42263 and 48058). Of these, the combinations GluR-1/GluR-2 and GluR-2/GluR-3 are the most frequent. The specific mechanism by which Perampanel exerts its antiepileptic effect in humans has not been fully elucidated.
Fycompa is a small molecule drug with a molecular mass of 349.4 g/mol, an AlogP of 3.57 , 3 rotatable bonds and does not violate the rule of 5. Canonical SMILES : O=C1N(C=C(C=C1c2ccccc2C#N)c3ccccn3)c4ccccc4
InChi: InChI=1S/C23H15N3O/c24-15-17-8-4-5-11-20(17)21-14-18(22-12-6-7-13-25-22)16-26(23(21)27)19-9-2-1-3-10-19/h1-14,16H
The recommended starting dose of Perampanel in the absence of other CYP3A4 enzyme-inducing antiepileptic drugs is 2 mg once daily taken orally at bedtime (and can be incremented to the recommended dose range of 8 mg to 12 mg once daily). The recommended starting dose of Perampanel in the presence of CYP3A4 enzyme-inducing antiepileptic drugs is 4 mg and patients should be monitored closely for response.
Perampanel is extensively metabolized via initial oxidation and sequential glucuronidation. Oxidative metabolism is mediated by CYP3A4 and/or CYP3A5 based on results of in vitro studies using recombinant human CYPs and human liver microsomes. Other CYP enzymes may also be involved.
The license holder is Eisai Inc. and the full prescribing information can be found here. -
Wellcome Trust Courses - Computational Resources For Drug Discovery 2013
Those of you who went on the course we ran this year will know how much fun it was - and from our perspective we're gonna keep on doing it till we get it right! So, once more, there is another chance to attend the course in 2013 - December 9 to 13th 2013 to be precise.
So if you are interested, pencil the dates in your diaries now, and set an automatic alarm for four months before, and check out the full course details then.
Of course, there are lots of other excellent courses in the same series, and the poster is available for download to display on your office wall here. -
The First Rule of Security Club is that you do not talk about Security Club
We worry about data security and privacy, a lot. I fret and sweat over this, and it is one of the things (alongside being late with EU reports) that genuinely keeps me awake at night, and that you can never know too much about (again a bit like the EU). We have started to collect examples of security and data privacy issues and vulnerabilities in online chemistry-related resources. Firstly, to build a set of real world examples, and to establish best practice for our own developers. It also allows us to potentially create an environment in which security and privacy matters can be privately discussed without the world being unnecessarily alerted to them; allowing fixes to be made, and generally keep the online chemistry world a better safer place.As would be expected for this sort of thing, the list will not be open, and not indexed in google (if it is right now, we’ve failed at step one!), so if you’re interested in joining the list, and your job involves the building/maintenance of online chemistry systems with a security/privacy responsibility, get in touch in the normal way.…. -
Clinical Development Candidate Annotatathon - July 2013
We are thinking of holding an annotatathon for clinical development stage compounds next July, here on campus at the EBI in Hinxton. At this event we will assign/curate efficacy targets for all the clinical stage compounds we have by then identified, simplifying the work by pre-clustering by chemical class/therapeutic area. Data generated during the event will be placed online immediately, and would of course be fully Open (none of this frustrating, online access only for us!).
If there is interest in taking part, and contributing to this effort, let me know! Depending on the level of interest, I may apply for funding to help with travel/accommodation. If you are interested in funding this we'd be delighted to help with this
