• Anyone in the Bay Area interested in a Chembl seminar in March 2010?


    We are speaking at the Spring ACS National meeting in San Francisco (in the polypharmacology section - it will almost exclusively be new slides!). This is in the week of March 21st to 25th 2010.

    If there is any interest in a seminar, database demo, or just a chat and (fine) coffee/(so-so) beer, it would be good to meet up, so mail me if you'd like to meet.

  • Chembl_02 - Press Release



    This morning, there was a press release released, marking the official release of chembl_02. More details are in the press release, but for the blog audience, the data is available in the interface, and the databases available for download on the ftp site. Work is already underway on chembl_03, with some associated minor changes to parts of the schema and additional curation of data. There is also something exciting and special in chembl_03, but more of that later.

    There is approximately 20% more data in chembl_02 than chembl_01 and new content highlights include a significant expansion of Natural Product records, and unification of all compound identifiers across all EMBL-EBI records (we use ChEBI ids) all chembldb compounds should now seemlessly and quickly make their way into PubChem.

    Many, many thanks to those who have told us of the errors and ambiguities you have found. We will incorporate all of these back into the database for the entire community.
    For newer readers a pointer, and for older readers with poor memory, a reminder, of the chembl FAQ, and keep an eye open of the chembl-og (or even better the RSS feed) for schema walkthroughs, support and so forth.

    Two pieces of staffing news for the group. Firstly, congratulations to Patricia for her success in getting selected for an EIPOD - this is for a joint collaborative project in peptide SAR between the Koehn and Overington groups. Secondly, we welcome our first PhD student - Felix Krueger, who is immersing himself in programming, databases, British life, and data.

    Complementary to the required formality of the press release - some thanks! The entire Chembl team would like to take this opportunity to thank our many friends and colleagues who have helped to date, and will do so in the future. In particular, the Wellcome Trust (especially Alan and Rebecca) for their vision and funding (and Janet, Chris, Henning and Bissan for their essential roles in the grant), the senior management of EMBL, especially Iain and Janet, for their wisdom and continuous support. We'd like to acknowledge the assistance our growing network of external curators (Malcolm, Sam, Lora, and Karen), previous interns (good luck Jigisha!), and outsourcing partners (especially Jignesh and the team). Bissan and Mark at the ICR were essential in the early days of the group, and achieved so much while we were recruiting, and they remain an important part of our work and plans. We also thank and recognise the management and staff of Inpharmatica and their investors, for much of the initial development of the databases was done at that time - you know who you are!. Prof. Hopkins, as ever, you are a star ;) Most essential though has been the friendship, focus and shared purpose of our new colleagues at the EMBL-EBI - especially our new friends in the ChEBI team, as well as the INTACT, Systems, Outreach, PANDA, HSF, EBI Industry programme partners, and many other new friends and colleagues, both at Hinxton and Heidelberg. Finally, finally; we have also been doubly blessed with 1) being able to continue working with several long-term collaborators, and 2) finding new important ones since starting at the EMBL-EBI. The future looks bright, so thank you all!

  • New Drug Approvals - Pt. XXIV - Bepotastine Besilate (Bepreve)

    We're mopping up a few drug approvals from 2009 we have not yet covered yet as monographs... Approved on September 8th 2009 was Bepotastine Besilate, marketed under the trade name Bepreve. Bepotastine is a topical, selective and non-sedating histamine (H1) receptor antagonist indicated in the treatment of itching associated with allergic conjunctivitis. Through the H1 binding, Bepotastine has broad range of anti-inflammatory effects - a stabilizing effect on mast cells, inhibition of eosinophil migration and interleukin-5 (IL-5), leukotriene B4 (LTB4) and platelet activating factor (PAF) release. Bepotastine has been previously approved in Japan, under the trade name Talion, for allergic rhinitis (2000) and urticaria and skin pruritus (2002). Bepotastine is a chirally pure, synthetic small molecule drug (Molecular Weight 388.89 g.mol-1 for Bepotastine itself and 547.06 g.mol-1 for the dosed besilate salt), is Rule-of-Five compliant and is delivered as an ophthalmic solution. Bepotastine has a low protein binding of approximately 55%, is minimally metabolized by CYP450 isozymes and elimination is mainly through renal excretion (approximately 75-90% excreted unchanged in urine). The recommended dosage is one drop directly to the infected eye(s) twice a day. The prescribing information can be found here. The structure (+)-4-[[(S)-p-chloro-alpha-2-pyridylbenzyl]oxy]-1-piperidine butyric acid, with no unusual reactive features. There is a single stereocenter in the structure, and Bepotastine is dosed as the (+) enantiomer. The physicochemistry will be dominated by the Zwitterionic nature of the molecule - a molecule of nett neutral charge, but which contains compensatory charge centers - in this case the basic nitrogen of the central piperidine ring, and the carboxylic acid (on the far right of the compound figure). 

    NAME="Bepotastine"
DRUG_TARGET="MSLPNSSCLLEDKMCEGNKTTMASPQLMPLVVVLSTICLVTVGLNLLVLYAVRSERKLHT
    VGNLYIVSLSVADLIVGAVVMPMNILYLLMSKWSLGRPLCLFWLSMDYVASTASIFSVFI
LCIDRYRSVQQPLRYLKYRTKTRASATILGAWFLSFLWVIPILGWNHFMQQTSVRREDKC
ETDFYDVTWFKVMTAIINFYLPTLLMLWFYAKIYKAVRQHCQHRELINRSLPSFSEIKLR
PENPKGDAKKPGKESPWEVLKRKPKDAGGGSVLKSPSQTPKEMKSPVVFSQEDDREVDKL
YCFPLDIVHMQAAAEGSSRDYVAVNRSHGQLKTDEQGLNTHGASEISEDQMLGDSQSFSR
TDSDTTTETAPGKGKLRSGSNTGLDYIKFTWKRLRSHSRQYVSGLHMNRERKAAKQLGFI
MAAFILCWIPYFIFFMVIAFCKNCCNEHLHMFTIWLGYINSTLNPLIYPLCNENFKKTFK
RILHIRS"
    SMILES="Clc1ccc(cc1)C(OC2CCN(CCCC(=O)O)CC2)c3ncccc3"
InChI="InChI=1S/C21H25ClN2O3/c22-17-8-6-16(7-9-17)21(19-4-1-2-12-23-19)27-18-
10-14-24(15-11-18)13-3-5-20(25)26/h1-2,4,6-9,12,18,21H,3,5,10-11,
13-15H2,(H,25,26)"
InChIKey="YWGDOWXRIALTES-UHFFFAOYSA-N"
ChemDraw=http://www.ebi.ac.uk/chembl/downloads/Bepotastine.cdx

    Bepreve is marketed by IstaVision and the product website is here
    
	  
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    Isn't Nature wonderful?
    
	  	
	  	

    

    Of course, the Nature journal is fantastic, but I was thinking of Nature, as in Mother, here. I came across this picture on the BBC news site. The original image (at an incredible 250m pixel size) is at http://rapidfire.sci.gsfc.nasa.gov/gallery/?2010007-0107/GreatBritain.A2010007.1150.250m.jpg
    

    Isn't it just wonderful!
    

    For reference, the EBI is roughly at the centre of the spiral cloud feature in the South-East corner of the UK.
    
	  
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    Links to/from chembldb
    
	  	
	  	

    

    If there are any cool or neat things that anyone has done with the chembldb data and is available on the web (either with an interface or as a web service) we are very happy to link to this from our pages. So if you have anything you want linked, let us know.
    
	  
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    Chembldb schema walkthrough - 3pm GMT, 15th January 2010
    
	  	
	  	

    

     We will host another web-meeting walkthrough of the chembldb core database schema on Friday 15th January at 3pm GMT. If you are interested in joining, please email us on this link for dial-in details. We will be using the webhuddle software for the demo so it may be worth trying it out on your machine beforehand.
    
	  
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    Species in Chembldb
    
	  	
	  	

    

    Thanks to Richard Bickerton at the University of Dundee here is a nice rendering of the species/genus/phyla of the targets in chembldb. Click the image to get a larger, readable view.
    

    
	  
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    Flibanserin, Polypharmacology, and HSDD
    
	  	
	  	

    

    There was an interesting news article in the latest Chemistry World (Volume 7, No 1, Jan 2010, p 15) on recent phase III disclosures for Flibanserin (which has quite complex pharmacology - a 5HT1A agonist, a 5HT2A antagonist and weak partial agonism at D4, Flibanserin was previously known by the research code BIMT-17). The recent clinical trials have the headline grabbing activity of potentially showing increase in female libido - labelled as HSDD (or Hypoactive Sexual Desire Disorder). Originally the compound was developed as an antidepressant, and it would appear that since several antidepressants 'decrease' sexual function and so clinicians were primed to look for side-effects on libido (for example, some SSRIs have the ability to  treat premature ejaculation). Unexpectedly, Flibanserin showed an increase in libido. So, potentially, with Flibanserin, there is another example of a serendipitous discovery (a nice overview of this area is provided in the OHE book pictured above and referenced below).
    

    There are many drugs of this 'anserin' class of potential drugs (the -anserin stem shows that the compounds have 5HT2 receptor antagonism as a major pharmacological activity (for example, 
    
Adatanserin, Altanserin, Benanserin, Blonanserin, Butanserin, Cinanserin, Eplivanserin, Fananserin, Flibanserin, Glemanserin, Iferanserin, Ketanserin, Lidanserin, Mianserin, Pelanserin, Pimavanserin, Pruvanserin, Ritanserin, Seganserin, and Tropanserin
    
- some of these are 'old' others 'new'). It would be astonishing if all of these have the same selectivity profile as Flibanserin, and also if Flibanserin has the 'optimal' profile for HSDD. So it is of interest to speculate if HSDD is a potential new indication for all/some of these other -anserins). A cursory view of the literature shows that many of these agents have broad activity across many pharmacologically relevant receptors, and so an interesting question, in the context of 'polypharmacology' is:
    

    • Which subset of -anserins have HSDD activity?
      

    • Is it possible to predict the next most similar profile compound to Flibanserin?
      

    • Would animal data be of any use in profiling/discovery of such compounds?
      

    %T Capturing the Unexpected Benefits of Medical Research
%E C. Pritchard
%I Office Health Economics
%D 2001

    
	  
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