• EMBL-EBI Small Molecule Bioactivity Course - Feb 2011


    Just posted on the EMBL-EBI website are the first details of the Small Molecule Bioactivity Course. There will be more details later, and the agenda needs sketching out in more detail, but the dates, and guest lecturers are all set. So, if you would like to take part in an introductory level course to the use of chemogenomics approaches to understanding biology and supporting healthcare research, keep an eye out for more details, or take a chance in case all the places go, and register now!

    On a related note, I would like to highlight the overall good-all-round-goodness and helpfulness of Noel O'Boyle; in honour, I may even go back to using the Irish form of my surname O'Verington.....

    The image above will mean little to most, but a lot to the few who watch UK kids TV.

  • ChEMBL_06 is live


    We're pleased to announce the release, a few moments ago of ChEMBL_06. This contains an additional 29,142 compound records and 138,348 new bioactivities. We've also done quite a lot of compound cleanup, names, research codes (vide infra), and so forth. A variety of database dumps are available from the public ftp site, and the live web database is now connect to ChEMBL_06.

    Additional data this release includes the standard literature data, but also the data from the brilliant Genomics of Drug Sensitivity in Cancer project, coordinated by Ultan McDermott at the Sanger Center (interested readers in the oncology area are also pointed to this previous blog post).

  • 2010 New Drug Approval - Pt. XI - Alcaftadine (Lastacaft)




    ATC code: 

    The summer got in the way of a timely post on this new drug. On 28 July 2010, Alcaftadine was approved for the treatment of patients with allergic conjunctivitis as a 0.25% opthalmic solution.
    This allergic reaction is most familiar in patients with hay fever but can also be caused by other allergens such as dust mites, moulds, perfumes etc. It causes red, itchy and watery eyes.
    Allergic conjunctivitis is caused by a type I hypersensitivity reaction of the immune system. Antigenic epitopes of the allergen are detected by IgE antibodies which mediate the excessive activation of mast cells and basophils.  The symptoms of allergic conjunctivitis are mainly caused by the release of histamine from these activated immune cells. Histamine increases the permeability of blood vessels and stimulates the activity of immune cells, through a number of differing histamine receptors.

    Alcaftadine and it's carboxylic acid metabolite (produced via a non P450 route) are antagonists of the H1 histamine receptor (Uniprot: P35367) and also inhibit histamine release.

    Alcaftadine is administered topically as a 0.25% solution. In a pharmakokinetics study, the plasma CMAX of Alcaftadine is 60pg/mL and occurs after 15 minutes, the plasma CMAX of the active metabolite is 10pg/mL and occurs after one hour. Plasma protein binding (ppb) for Alcaftadine is 39.2%, and for the carboxylic acid metabolite is 62.7%. The elimination half-life of the metabolite is appoximately 2 hours. The presence of the aldehyde is an unusual chemical feature in Alcaftadine, since aldehydes are usually quite reactive, as would be expected this group is readily metabolized to a carboxylic acid.

    The full prescribing information is here.

    Adverse reactions may include eye irritation, eye redness, nasopharyngitis, headache and influenza.




    IUPAC: 11-(1-methylpiperidin-4-ylidene)-5,6-dihydro
    imidazo[2,3-b][3]benzazepine-3-carbaldehyde
     
    SMILES: CN1CCC(CC1)=C2c3ccccc3CCn4c(C=O)cnc24
    InChI: 1S/C19H21N3O/c1-21-9-6-15(7-10-21)18-17-
    
5-3-2-4-14(17)8-11-22-16(13-23)12-20-19(18)22/
    
h2-5,12-13H,6-11H2,1H3
     
    Alcaftadine was developed by the Janssen Research Foundation and will be marketed in the US under the name Lastacaft by Vistakon Pharmaceuticals.
    
	  
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    Innovation and Ownership in Drug Discovery by Country (maybe, perhaps, well maybe not then!)
    
	  	
	  	
    I've been looking at the Research Code data recently, and here is an interesting plot. It is the counts of Research Codes classified by Country. It is a first, look-see plot, based on currently incomplete data, but I think it is quite interesting nonetheless.
    

    


    
A basic assumption behind the assignment of a distinct research code stem is that they reflect an autonomous entity with the aim of discovering drugs. Today the majority of newly founded entities will be funded by private/VC money, and these will be acquired by a larger company once some degree of commercial success, or anticipated commercial potential has been achieved. Our data is a 'blend' of recent and historical data, and over time, the structure and scale of research has changed (a smaller number of companies in the distant past, and a larger number from the mid 1990s onwards as a large number of biotechs were established; also there will be differences across various countries).
    

    
The way we have collected the research codes (773 of them so far) will focus on clinical stage compounds, and therefore the ability of that company and associated infrastructure to move compounds through into clinical development. In our tables the research code has a 'currently controlling company' assigned to it, and this company has a 'country' assigned to it - this is the location of its corporate headquarters, and to a first approximation will record where the controlling rights/IP is now held (ignoring any specific licensing deals that have been done over specific drugs). Of course, the location of the headquarters does not reflect where the work is, or has been historically, done. Many current companies have multiple research codes, for example Pfizer has 32 distinct historical research codes, and this count will correlate with a number of mergers and acquisitions over time; these mergers will sometimes switch 'ownership' from one country to another.
    

    
The distribution follows a classic power-law distribution (80:20 rule, or a whole bunch of other similar names) -  specifically, six countries (of 27) cover 86% of research code stems (the USA, Japan, Germany, France, the UK and Switzerland). To my mind there are a few surprises; for example, the relatively high rank of Japan - this may reflect a complex corporate history of mergers, there are certainly few biotechs in Japan producing clinical candidates; but I just don't know yet. Secondly, Sweden seems lower than I would have expected, but this may be down to mergers transferring 'corporate ownership' from one country to another (Astra and Pharmacia). Conversely, Italy seems higher than I would have initially predicted - but maybe I don't know the history of the industry as well as I should.
    

    
Another obvious feature is the low current rank of India and China - although a lot of basic research and outsourcing is done in these territories now, very little of this is currently owned and coordinated by companies headquartered there.
    

    
I've given up on trying to use google docs for any of this stuff - it is not that stable for me, and so if anyone is interested in the underlying spreadsheet, mail me....
    
	  
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    Current GPCR X-ray structures
    
	  	
	  	
    As part of resurrecting GPCR SARfari from the ashes, we needed to refresh the protein structure content. There are now a surprisingly large number of distinct X-ray family A, rhodopsin-like GPCR structures known, of course it is never enough, but large nonetheless. There are five distinct proteins (bovine and squid rhodopsin, human beta-2 adrenergic receptor, turkey beta-1 adrenergic receptor and human Adenosine A2A receptor. These are known in a variety of different liganded states, crystal forms, resolutions, and also with differing numbers of distinct chains within crystallographic assymmetric units. So in total, there are 27 distinct X-ray PDB entries and 45 distinct GPCR domain structures.
    

    
Here is a table, as of 27th August 2010.
    

    

    

    PDB codeCh.ProteinLigandSpeciesRes.Date
    

    1f88ARhodopsinretinalBos taurus2.84 Aug 2000
    

    1f88BRhodopsinretinalBos taurus2.84 Aug 2000
    

    1gzmARhodopsinretinalBos taurus2.620 Nov 2003
    

    1gzmBRhodopsinretinalBos taurus2.620 Nov 2003
    

    1hzxARhodopsinretinalBos taurus2.84 Jul 2001
    

    1hzxBRhodopsinretinalBos taurus2.84 Jul 2001
    

    1l9hARhodopsinretinalBos taurus2.615 May 2002
    

    1l9hBRhodopsinretinalBos taurus2.615 May 2002
    

    1u19ARhodopsinretinalBos taurus2.212 Oct 2004
    

    1u19BRhodopsinretinalBos taurus2.212 Oct 2004
    

    2g87ARhodopsinretinalBos taurus2.62 Mar 2006
    

    2g87BRhodopsinretinalBos taurus2.62 Mar 2006
    

    2hpyARhodopsinretinalBos taurus2.818 Jul 2006
    

    2hpyBRhodopsinretinalBos taurus2.818 Jul 2006
    

    2pedARhodopsinretinalBos taurus2.92 Apr 2007
    

    2pedBRhodopsinretinalBos taurus2.92 Apr 2007
    

    2i36ARhodopsinapoBos taurus4.117 Oct 2006
    

    2i36BRhodopsinapoBos taurus4.117 Oct 2006
    

    2i36CRhodopsinapoBos taurus4.117 Oct 2006
    

    2i37ARhodopsinapoBos taurus4.117 Oct 2006
    

    2i37BRhodopsinapoBos taurus4.117 Oct 2006
    

    2i37CRhodopsinapoBos taurus4.117 Oct 2006
    

    2j4yARhodopsinretinalBos taurus3.425 Sep 2007
    

    2j4yBRhodopsinretinalBos taurus3.425 Sep 2007
    

    3capARhodopsinapoBos taurus2.924 Jun 2008
    

    3capBRhodopsinapoBos taurus2.924 Jun 2008
    

    3c9lARhodopsinretinalBos taurus2.65 Aug 2008
    

    3c9mARhodopsinretinalBos taurus3.416 Feb 2008
    

    3dqbARhodopsinapoBos taurus3.223 Sep 2008
    

    2z73ARhodopsinretinalTodarodes pacificus2.513 May 2008
    

    2z73BRhodopsinretinalTodarodes pacificus2.513 May 2008
    

    2ziyARhodopsinretinalTodarodes pacificus3.727 Feb 2008
    

    2r4rAbeta-2 adrenergic receptorapoHomo sapiens3.46 Nov 2007
    

    2r4sAbeta-2 adrenergic receptorapoHomo sapiens3.46 Nov 2007
    

    2rh1Abeta-2-adrenergic receptorCarazololHomo sapiens2.430 Oct 2007
    

    3d4sAbeta-2 adrenergic receptorTimololHomo sapiens2.817 Jun 2008
    

    3kj6Abeta-2 adrenergic receptorapoHomo sapiens3.416 Feb 2010
    

    3ny8Abeta-2 adrenergic receptorICI-118551Homo sapiens2.811 Aug 2010
    

    3ny9Abeta-2 adrenergic receptornovel analog of ICI-118551Homo sapiens2.811 Aug 2010
    

    3nyaAbeta-2 adrenergic receptorAlprenololHomo sapiens3.211 Aug 2010
    

    2vt4Abeta-1 adrenergic receptorCyanopindololMeleagris gallopavo2.724 Jun 2008
    

    2vt4Bbeta-1 adrenergic receptorCyanopindololMeleagris gallopavo2.724 Jun 2008
    

    2vt4Dbeta-1 adrenergic receptorCyanopindololMeleagris gallopavo2.724 Jun 2008
    

    2vt4Cbeta-1 adrenergic receptorCyanopindololMeleagris gallopavo2.724 Jun 2008
    

    3emlAAdenosine A2a receptorZM-241385Homo sapiens2.614 Oct 2008
    

    
	  
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    More Research Code Stems
    
	  	
	  	

    

    
Many thanks to those of you who have sent in research code stems! I have updated this page, with about another 70, and the full table should shortly be accessible in chembldb.
    
	  
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    SMR Meeting On Epigenetics - 22nd September 2010
    
	  	
	  	

    
Drat! It's almost as if the SMR committee look at my Google calendar and book all their meetings on days when I'm otherwise occupied.....
    

    
Anyway, on Wednesday September 22nd 2010 the SMR are holding a meeting on Epigenetics, one of the hottest current areas of disease biology, at the NHLI, further details here.
    
	  
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    Druggability assessment
    
	  	
	  	
    Here are a couple of references for some work on computer-based target assessment we have been involved in.
    

    %T The Molecular Basis of Predicting Druggability
%A Al-Lazikani, B.
%A Gaulton, A.
%A Paolini, G.
%A Lanfear, J.
%A Overington, J.
%A Hopkins, A.
%I Wiley-VCH Verlag GmbH
%O http://dx.doi.org/101002/9783527619368.ch36
%O DOI 10.1002/9783527619368.ch36
%P 1315-1334
%B Bioinformatics - From Genomes to Therapies
%E Lengauer, T.
%O ISBN: 978-3-527-31278-8
%D 2007

%T The Molecular Basis of Predicting Druggability
%A Al-Lazikani, B.
%A Gaulton, A.
%A Paolini, G.
%A Lanfear, J.
%A Overington, J.
%A Hopkins, A.
%I Wiley-VCH Verlag GmbH
%O http://dx.doi.org/10.1002/9783527619375.ch14b
%O DOI 10.1002/9783527619375.ch14b
%P 804-823
%B Chemical Biology: From Small Molecules To Systems Biology and Drug Design
%E Schreiber, S.L., Kapoor, T.M., & Wess, G.
%O ISBN: 978-3-527-31150-7
%D 2007

    
	  
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