• PhD Studentship Available for Oct 2010 Intake

    The ChEMBL group has a further PhD studentship available for intake in fall 2010. If you are interested, the registration deadline is 1st December 2009, with a final Application Deadline of 15th December 2009. A wide variety of projects are available and we encourage students to propose their own ideas for their studies.

    Previous Chembl-og posts on studentships/projects, etc. are here

    An application form is available here

    For further details of the EMBL PhD program, in particular funding eligibility and so forth please click here

  • For the Cambridge (UK) Locals.... (UPDATED)

    DUE TO INDUSTRIAL ACTION THE TALK BY CHRIS HAS BEEN RESCHEDULED TO 3PM ON FRIDAY 16TH OCTOBER - IN ROOM M/203.

    On Monday 19th October, in the morning, we have a visit from Chris Lipinski, of the 'Rule of Five' fame. The talk will be advertised on campus, but guests are welcome as well - it's just that I will need to tell security the names and affiliation of any visitors by Friday 16th October.

    On this occasion the talk is titled "The good, the bad and the unknown in drug discovery: a very opinionated discussion".

    If you are interested in coming, mail me.

    Of course the photo above is not of Chris, but he does look strangely familiar ;)

  • New Drug Approvals - Pt. XIX - Pralatrexate (Folotyn)



    Also approved on September 25th was Pralatrexate (tradename Folotyn). Pralatrexate is the first drug approved for the treatment of Peripheral T-Cell Lymphoma (PTCL), an aggressive form of non-Hodgkins lymphoma. Lymphoma is a cancer that begins in the lymphocytes of the immune system. PTCL is a rare disease, occurring in around 9,500 patients each year in the United States.
    Pralatrexate, also known as PDX, is a folic analog that competitively inhibits dihydrofolate reductase (DHFR). Since Pralatrexate blocks the use/function of a metabolite, it is also an antimetabolite. Pralatraxate has high affinity for the folate transporter SLC19A1 (also known as RFC-1), and so is an example of a drug that is 'actively transported', and is also a substrate for polyglutamation by the enzyme folylpolyglutamate synthase (FPGS). Once polyglutamated Pralatrexate has a prolonged intracellular half-life, giving prolonged action in malignant cells. Pralatrexate is related to several other drugs, most notably Methotrexate, and 'old' launched drug, and also the clinical stage compounds - Ketotrexate, Edatrexate, and also the antiprotozoal agent Trimetrexate, all of which are DHFR inhibitors.
    Pralatrexate is a polar, racemic small molecule (Molecular Weight of 477.5 g.mol-1), soluble in aqueous solutions. Pralatrexate is a mixture of diastereomers (stereoisomers that are not enantiomers, i.e. they are non-superimposable). Diastereomers can have different physical properties biological activities, and different reactivity. Pralatrexate has a volume of distribution (Vd) of 105L and 37L for the S- and R-diastereomers, respectively, a plasma protein binding (ppb) of 67%, a systemic clearance of 417 mL.min-1 (S-diastereomer) and 191 mL.min-1 (R-diastereomer), and an elimination half-life (T1/2)of 12-18 hours. Pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases, and has low potential to induce or inhibit the activity of CYP450 isozymes - elimination is primarily of unchanged drug in urine.
    The recommended dosing of Pralatrexate is 30 mg.m-2 administrated as an intravenous injection once weekly for 6 weeks in 7-week cycles. The full prescribing information can be found here.

    The structure (2S)-2-[[4-[(1RS)-1-[(2, 4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid is a folate analog in which the hydroxyl group of the pyrimidine ring has been replaced by an amine, and the central amino group of the molecule has been replaced by a stereocenter carbon with a methylacethylene attached to it (which may undergo nucleophilic atack). Pralatrexate diastereomers differ in configuration at this stereocenter only, and so they are also epimers. 
    <CHEMBL_DRUG>
<DRUG_NAME="Pralatrexate" TRADEMARK_NAME="Folotyn" APPROVAL_DATE="25-SEPT-2009" DRUG_MOLECULAR_WEIGHT=477.5>
<DRUG_STRUCTURE>
<DRUG_SMILES="O=C(O)[C@@H](NC(=O)c1ccc(cc1)C(CC#C)Cc2nc3c(nc2)nc(nc3N)N)CCC(=O)​O">
<InChI="InChI=1/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18
(27-15)19(24)29-23( ​25)30-20)12-4-6-13(7-5-12)21(33)28-16
(22(34)35)8-9-17(31)32/h1,4-​ 7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,3​ 0)/t14?,16-/m0/s1">
<InChIKey="OGSBUKJUDHAQEA-WMCAAGNKSA-N">
</DRUG_STRUCTURE>
<ChemDraw="Pralatrexate.cdx">
<DRUG_TARGET>
VGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFSI
PEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSSV
YKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKFE
VYEKND
</DRUG_TARGET>
</CHEMBL_DRUG>
    The license holder is Allos Therapeutics, Inc. and the product website is www.folotyn.com.

  • New Drug Approvals - Pt. XVIII - Ustekinumab (Stelara)

    Recently approved by the FDA, on September 25th 2009, was Ustekinumab, marketed under the trade name Stelara. Ustekinumab, previously known as CNTO-1275, is a first-in-class injectable biological drug blocking signalling of two distinct interleukins (IL-12 and IL-23) and is indicated for the treatment of adults with moderate to severe plaque psoriasis. Psoriasis (ICD-10: L40) is a complex autoimmune disease, typically leading to the formation of scaly red or silvery-white plaques on the skin. Another drug with the same mechanism as Ustekinumab (blocking IL-12 and IL-23 signalling) is ABT-874, ABT-874 is currently still in clinical trials.
    Ustekinumab is dosed as a subcutaneous injection given at weeks 0 and 4, followed subsequently by every-12-week maintenance dosing. The recommended starting dose of is 45 mg for patients weighing 100 kg or less, and 90 mg for patients weighing more than 110 kg (the 45mg dose corresponds to a 0.31 umol dose).
    Ustekinumab is is a human IgG1қ monoclonal antibody and is the first drug to target IL-12 and IL-23 cytokines, these are two naturally occurring secreted, heterodimeric proteins (two distinct proteins (themselves derived from two distinct genes) bound in a specific complex), they are involved in inflammatory and immune responses, such as the activation of CD4+ and Natural Killer T-cells. Ustekinumab binds with high affinity and specificity to the p40 protein shared as a common subunit by both IL-12 and IL-23. Through targeting the shared p40 component, Ustekinumab is able to block signalling by both interleukins. IL-12 and IL-23 eventually signal via master inflammatory system regulators tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB). 
    <CHEMBL_DRUG>
<DRUG_NAME="Ustekinumab" TRADEMARK_NAME="Stelara" RESEARCH_CODE="CNTO1275" APPROVAL_DATE="25-SEPT-2009" DRUG_MOLECULAR_WEIGHT="145650">
<DRUG_SUBUNIT="Heavy gamma-1 chain">
EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWLGWVRQMPGKGLDWIGI
MSPVDSDIRYSPSFQGQVTMSVDKSITTAYLQWNSLKASDTAMYYCARRR
PGQGYFDFWGQGTLVTVSSSSTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
</DRUG_SUBUNIT>
<DRUG_SUBUNIT NAME="Light kappa chain">
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPYTFGQ
GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG
LSSPVTKSFNRGEC
</DRUG_SUBUNIT>
<DRUG_TARGET UNIPROT="P29460" TARGET_NAME="p40 subunit of IL-12 and IL-23">
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSG
KTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKE
PKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGA
ATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYEN
YTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLT
FCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW
ASVPCS
</DRUG_TARGET>
</DRUG>
</CHEMBL_DRUG>
    The license holder for Ustekinumab is Johnson & Johnson. and the product website is www.stelarainfo.com.

  • ChEMBL Internships

    We regularly get request for internships in our group, and we are keen to host suitable scientists from a broad range of molecular informatics and IT backgrounds. These visits are typically for from two to three months in our lab here at the EMBL-EBI, and there is always lots of work to be done. We can provide modest financial support, but cannot cover travel costs to/from the UK.

    If you wish to apply, please use this link and 1) attach a current and accurate cv/resume, 2) state when you are available to work, and 3) (MOST IMPORTANT) what you would like to achieve during your time with us.

  • Chemical Toolbox

    We are interested in putting some compound availability data into the ChEMBL databases, nothing really fancy or large scale, maybe just a few thousand compounds - our focus will be on 'tool compounds' - key literature standards for specific targets, etc. So if any compound vendors with sets of these compounds are interested in being included, please contact us.

  • New Drug Approvals - Pt. XVII - Telavancin (Vibativ)

    The latest new drug approval, on 11th September 2009 was Telavancin - which was approved for the treatment of adults with complicated skin and skin structure infections (cSSSI) caused by susceptible Gram-positive bacteria, including Staphylococcus aureus, both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains. Telavancin is also active against Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus) and Enterococcus faecalis (vancomycin susceptible isolates only). Telavancin is a semisynthetic derivative of Vancomycin. Vancomycin itself is a natural product drug, isolated originally from soil samples in Borneo, and is produced by controlled fermentation of Amycolatopsis orientalis - a member of the Actinobacteria.

    Telavancin has a dual mechanism of action, firstly it inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycan - the mesh like outer membrane of the bacteria. It achieves this effect in a similar manner to the mechanism of Vancomycin. Vancomycin (and Telavancin) prevent the incorporation of NAM (N-acetylmuramic acid) and NAG (N-acetylglucosamine) subunits into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls. Secondly, Telavancin binds to the bacterial membrane and disrupts membrane barrier function.

    Telavancin is a lipoglycopeptide antibiotic, and is semisythetic, being a derivative of the natural product Vancomycin, it has a molecular weight of 1755.6g.mol-1, as would be expected from a compound of this size, it comprehensively fails all the components of the Rule-of-Five. Telavancin is lipophillic and as expected, is not highly soluble in water. Following injection, Telavancin has a volume of distribution of 145mL/kg, a plasma half-life of 8hr and a clearance of 13.9mL/hr/kg.

    Telavancin is available in the form of a reconstitutable powder for injection. Recommended dosage and full prescribing information can be found here. A course of treatment usually last seven or fourteen days and is a once daily dose of 10mg/kg (given as an hour long infusion). For a 'typical' adult of mass 70kg, this is a once daily dose of 700mg, this equates to a relatively large molar dosage (ca. 400umol).

    Telavancin has a boxed warning.

    Televancin has a complicated tricyclic structure, there are seven amino-acids as the core of the structure (the 'peptide' part of the lipoglycopeptide name), there are two sugar rings (the 'glyco' part of the name), and then, on the right hand part of the image above, a long lipophillic chain (the 'lipo' part of the lipoglycopeptide name). The biosynthesis of the parent natural product is fascinating, and is covered here. The specific differences of Telavancin compared to Vancomycin are the addition of the lipophillic alkyl chain, and the addition of the phosphate group (in the bottom right of the image). The glycopeptide antibiotic class of drugs include other Vancomycin derivatives, for example, Teicoplanin (launched as Targocid), Oritavancin (phase III trials), Dalbavancin (phase III trials) and the more chemically dissimilar Ramoplanin (phase III trials). 

    <NAME="Telavancin" >
<SMILES="CCCCCCCCCCNCCNC1(CC(OC(C1O)C)OC2C(C(C(OC2OC3=C4C=C5C=C3OC6=C(C=C(C=C6)C(C(C(=O)NC(C(=O)NC5C(=O)NC7C8=CC(=C(C=C8)O)C9=C(C(=C(C=C9C(NC(=O)C(C(C1=CC(=C(O4)C=C1)Cl)O)NC7=O)C(=O)O)O)CNCP(=O)(O)O)O)CC(=O)N)NC(=O)C(CC(C)C)NC)O)Cl)CO)O)O)C">
<InChI="InChI=1S/C80H106Cl2N11O27P/c1-7-8-9-10-11-12-13-14-21-85-22-23-87-80(5)32-57(115-37(4)71(80)103)119-70-68(102)67(101)55(34-94)118-79(70)120-69-53-28-41-29-54(69)117-52-20-17-40(27-46(52)82)65(99)63-77(109)91-61(78(110)111)43-30-50(96)44(33-86-35-121(112,113)114)66(100)58(43)42-25-38(15-18-49(42)95)59(74(106)93-63)90-75(107)60(41)89-73(105)48(31-56(83)97)88-76(108)62(92-72(104)47(84-6)24-36(2)3)
64(98)39-16-19-51(116-53)45(81)26-39/h15-20,25-30,36-37,47-48,55,57,59-65,67-68,70-71,79,84-87,94-96,98-103H,7-14,21-24,31-35H2,16H3,(H2,83,97)(H,88,108)(H,89,105)(H,90,107)(H,91,109)(H,92,104)(H,93,106)(H,110,111)(H2,112,113,114)/t37-,47+,48-,55+,57-,59+,60+,61-,62+,63-,64+,65+,67+,68-,70+,71+,79-,80-/m0/s1" >
<InChIKey="ONUMZHGUFYIKPM-MXNFEBESSA-N" >
<ChemDraw=Telavancin.cdx >

    The license holder is Theravance and www.vibativ.com is the product website.

  • EU Innovative Medicines Initiative (IMI) 2nd call

    The European Commission and EFPIA (European Federation of Pharmaceutical Industries and Associations) has recently announced the 2nd round of the Innovative Medicines Initiative (IMI) scheme, the amount of funding available is quite substantial, but arguably more important to the research community is the embracing of open data and services, and in particular coordinated pre-competitive activities (there is a lovely recent paper on these sort of activities here, a subscription may be required) 

    %J Nature Rev. Drug Discov. 
%D 2009
%P 701-708
%T Lowering industry firewalls: pre-competitive informatics initiatives in drug discovery
%A Barnes MR
%A Harland L
%A Foord SM
%A Hall MD
%A Dix I
%A Thomas S
%A Williams-Jones BI
%A Brouwer CR

    To quote from the EU Commissioner of Science and Research, Janez Potocnik.

    "We should see results from this exciting new research mechanism very soon and [...] new innovative medicines should reach European patients faster"

    To quote from Bill and Ted

    "Most excellent!"

    The website for IMI is http://imi.europa.eu, and details of the second call are here