• USAN Watch - March 2012

    The USANs for March 2012 have just been published.

    USAN Research Code StructureDrug ClassTherapeutic classTarget
    abediterol, abediterol napadisylateLAS-100977synthetic small moleculetherapeutic
    beta 2 receptor
    gemcitabine elaidateCP-4126natural product derived small molecule prodrugtherapeuticDNA replication
    golvatinib, golvatinib tartrateE-7050synthetic small moleculetherapeuticMET, VEGFR2
    naldemedine tosylatenatural product derived small moleculetherapeuticopioid receptors
    ocaratuzumabAME-133v, LY-2469298mAbtherapeuticCD20
    quisinostat hydrochlorideJNJ-26481585, JNJ-26481585-AACsynthetic small moleculetherapeuticHDACs
    setipiprantACT-129968synthetic small moleculetherapeuticCRTH2
    tildipirosinZuprevonatural product derived small moleculetherapeutic50S ribosome
    tirasemtivCK-2017357synthetic small moleculetherapeutictroponin activator
    zicronapine, zicronapine succinateLu-31-130synthetic small moleculetherapeuticD1, 5HT2A receptors

    All are human, with the exception of Tildipirosin, which is intended for bovine use.

  • PPI Library - Part 2


    Boy that was a big sandwich; but now I have some time in bed, inbetween the rest of my life to do a 15 minute blog post, and I really need a break from stressing over non-science stuff.

    So here's some more background to what I'm interested in doing here - coming up with peptidomimetics that completely (to some level of approximation) cover accessible peptide conformational space. Here's an example of a series of inhibitors complexed to thrombin, firstly from underneath (imagine you were inside the protein looking out).


    This is now almost a classic case of drug design, so much work has been done in the area, and frankly quite abysmal translation through to effective drugs. Some of the preclinical work I was involved in is here (subscription required). Thrombin was a tough target to get right, both from a chemistry, and as it also turns out, a biology perspective. Back to the PPI subject though - there are two high efficiency pockets in thrombin - the 'P1' pocket that binds the Arg/Lys of substrates, and an 'aryl site' that binds hydrophobic (and generally as the name would suggest aryl groups). In between these two pockets is a 'saddle' of thrombin main-chain that needs to be traversed (the Donor - Acceptor - Donor annotation) - and for our purposes there is this interesting donor acceptor donor feature complementary to main chain hydrogen bonding features (which are used to bind the peptide main chain in substrates). It is notable that these DAD and ADA (and usually not too much longer) triplets are really common in PPIs, and have a certain recurrent spacing between them - complementary to the spacing of the restricted composition protein receptors for most drugs. In my view, there will be 'magic' - or more accurately useful spacings of donor-acceptor features in peptidomimetics - and more importantly a barren far larger wasteland of chemical sensible and possible donor-acceptor spacings, that just don't fit the majority of protein receptor possible interactions - in fact it's interesting to speculate whether this acceptor-donor spacing is a useful parameter for chemical space display. You can imagine an interesting thing to look at would be to take a set of pharmacophores and then scramble feature properties and investigate whether close D-D are rarer than they could be, D-A commoner, etc., ....

    I said the thrombin example is a little bit like a saddle - well here's a view looking down the backbone ridge of thrombin which hopefully makes in clearer - we can only see one of the donor features in this view, other is occluded due to the curve shape of the backbone.


    Of course, this particular example is a beta-mimic, and there are many other classes of PPIs - some involving the main chain (primarily beta-strand and turns as we'll see in a later post) and others not involving backbone interactions (primarily alpha-helix mimics) - Remember though that these hydrogen bonds don't buy you much potency under usual conditions, they are almost a necessary evil with respect to potency, so we don't want to got too mad in factoring them into our designs as a source of affinity - but they do help lower logP which is always a useful thing - so small polar scaffolds are the best thing to aim for. Loads of people will be incensed by the previous simplifications and assumptions - well this is a blog post, not a paper, so feel free to add comments if you fancy!

    One site of particular interest in this area is the TIMBAL database from the group of Tom Blundell.
    Atomic interactions and profile of small molecules disrupting protein-protein interfaces: the TIMBAL database - these contain a bunch of specific examples that we wish to mimic with this PPI library.

    %T Atomic interactions and profile of small molecules disrupting protein-protein interfaces: the TIMBAL database
%A A.P. Higueruelo
%A A. Schreyer
%A G.R. Bickerton
%A W.R. Pitt
%A C.R. Groom
%A T.L. Blundell
%J Chem Biol Drug Des.
%D 2009
%V 74
%P 457-67

    Oh, I think I managed to convince my train-buddy Roman that this is an interesting problem, and he is planning to look into another part of the analysis - which is good news. 

  • New Drug Approvals 2012 - Pt. VII - Lucinactant (SurfaxinTM)








    ATC code: R07AA30


    On March 6, the FDA approved Lucinactant (previously known as KL4-surfactant and ATI 02) for the prevention of infant respiratory distress syndrome (IRDS), which occurs in premature infants with an incidence of 1%. The onset of IRDS is shortly after birth and it typically lasts 2-3 days. Symptoms include shortness of breath, increased heart rate and bluish discoloration of the skin (cyanosis). IRDS can lead to serious complications such as chronic changes of the lung structure, acidosis, intracranial hemorrhage and an incomplete closure of the vascular connection between the aorta and the pulmonary artery (patent ductus arteriosus). In developed countries, IRDS is one of the leading causes of death in the first month after birth.

    IRDS is caused by insufficient production of surfactant, a substance that is secreted into the air-filled alveoli of the lung by specialized cells called type II pneumocytes. The lack of surfactant causes an increased surface tension on the interface between the capillary blood vessels (and embedding alveolar tissue) and the air-filled lumen of the alveolus. This results in a contraction of the air-space and obstructs normal breathing.

    Lucinactant is a substitute for endogenuous surfactant that is administered via a intratracheal tube. Unlike other formulations on the market such as beractant, poractant and calfactant - which are animal derived - Lucinactant is a synthetic formulation consisting of a mixture of phospholipids, fatty acids and a synthetic peptide called sinapultide. Sinapultide is a hydrophobic peptide composed of 17 leucine residues and 5 lysine residues. The peptide is designed to mimick the properties of apolipoprotein SP-B (Uniprot P07988). The remaining components of Lucinactant are palmitic acid and the phospholipids DPPC and POPG.

    palmitic acid


    DPPC


    POPG
    Sinapultide

    Palmitic acid (CHEMBL82293) is a fatty acid with molecular weight 256.42 Da.
    IUPAC name: Hexadecanoic acid
    Canonical SMILES: CCCCCCCCCCCCCCCC(=O)O
    InChI=1S/C16H32O2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16(17)18/h2-15H2,1H3,(H,17,18)

    DPPC  (CHEMBL1200737) is a phospholipid with molecular weight 734.06Da.
    IUPAC name: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine
    Canonical SMILES: CCCCCCCCCCCCCCCC(O[C@@H](COP([O-])(OCC[N+](C)(C)C)=O)COC(CCCCCCCCCCCCCCC)=O)=O
    InChI=1S/C40H80NO8P/c1-6-8-10-12-14-16-18-20-22-24-26-28-30-32-39(42)46-36-38(37-48-50(44,45)47-35-34-41(3,4)5)49-40(43)33-31-29-27-25-23-21-19-17-15-13-11-9-7-2/h38H,6-37H2,1-5H3/t38-/m1/s1

    DOPG is a phospholipid with molecular weight 747.50 Da.
    IUPAC name: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol
    Canonical SMILES: CCCCCCCC/C=C\CCCCCCCC(O[C@@H](COP(OCC(CO)O)([O-])=O)COC(CCCCCCCCCCCCCCC)=O)=O
    InChI=1S/C40H77O10P/c1-3-5-7-9-11-13-15-17-18-20-22-24-26-28-30-32-40(44)50-38(36-49-51(45,46)48-34-37(42)33-41)35-47-39(43)31-29-27-25-23-21-19-16-14-12-10-8-6-4-2/h17-18,37-38,41-42H,3-16,19-36H2,1-2H3,(H,45,46)/p-1/b18-17+/t37?,38-/m1/s1

    Sinapultide is a synthetic peptide of 21 amino acids with molecular weight 2469.46 Da.
    Sequence: KLLLLKLLLLKLLLLKLLLLK
    CAS: 138531-07-4

    It is of note that Lucinactant is a USAN which is a mixture of four distinct components (without a defined composition in the USAN document). This creates a surprising number of issues in the storage and retrieval of drug information (sigh), and this sort of thing is dragging us towards defining a ChEMBL USAN-like data object for use in our systems (double sigh). Sinapultide has its own distinct assigned USAN, but DPPC, Palmitic acid and DOPG do not (or not that I can find).

    Lucinactent is an off-white gel at the recommended storage temperature of 2-8 C  but becomes a liquid when warmed before use. Each mL of SURFAXIN contains 22.50 mg DPPC and 7.50 mg POPG, Na, 4.05 mg palmitic acid, and 0.862 mg sinapultide in tromethamine and sodium chloride. It is recommended that a maximum of 4 doses at 5.8 mL/kg is administered within 48 h after onset of IRDS, within intervals of at least 6h.

    Pharmakokinetics of Lucinactent were not studied in humans. A study into the treatment of adult respiratory distress syndrome (ARDS) resulted in increased mortality rate of treated patients. Lucinactent is not indicated for the treatment of ARDS.

    Lucinactent is marketed by Discovery Labs Inc. under the name Surfaxin. Full prescribing information can be found here.


  • A reminder of the course being held on campus here in early July - the joint EMBL-EBI and Wellcome Trust Resources for Computational Drug Discovery.

  • ChEMBL Webinars

    For those of you who want to sign up to the ChEMBL webinars that are planned for the coming months, we have now set up a Doodle Poll that you can use to register your interest. Please note that the Doodle Poll is hidden, so only the ChEMBL Team can see who has signed up. Make sure that you leave both your **name** and **email address** in the 'Your Name' field so that someone from ChEMBL Help can get back to you with the connection details.

  • Meeting: ECBS2012 - 3rd European Chemical Biology Symposium


    There's a great meeting in central Europe this summer, from the 1st to 3rd July 2012 - the 3rd European Chemical Biology Symposium/ 2nd Vienna Drug Action Conference, held at the Festive Hall of the Austrian Academy of Sciences, Vienna, Austria. http://ecbs2012.cemm.at/

  • Webinar Reminder

    This is a quick reminder for all ChEMBL users that the first in our new series of webinars will be starting tomorrow at 15:30 (UK local time). Tomorrows topic is Interface and Searching. There is still time to register for this webinar and all future ones, if you email us at chembl-help.

  • PPI Library - part 1


    Some Open Science - Yay! A sort of research journal for a small project involving structural bioinformatics and cheminformatics.

    So here is an approach to looking in a systematic way at peptidomimetics, specifically those that have the potential to serve as the basis for the design of small-molecule non-peptide-based ligands for the modulation of protein-protein interactions (PPIs).

    The design principle is to:

    1) Identify peptide conformations important in PPIs.
    2) Find small molecule scaffolds that display the 'side-chains' with a given geometry in a way that mimic the conformations found in 1).

    The idea here is to be as general and comprehensive as possible, and also provide some ability to understand the effects of cutoffs and parameters that inevitably will be applied in this sort of work.

    It's actually quite difficult to identify a set of PPIs - I have some ideas, but they rely on me roping in some colleagues (Roman) to do it in an easy way. We also need to split, for now, the contiguous epitope from the distributed epitope case - we'll look at the discrete epitome case first. This is where sequentially adjacent residues interact with the target. So let's be super general and look at all peptide conformations observed in a large set of proteins - the protein-protein interaction ones will be a subset of these, and we can tag them up later, and probably teasing apart the features of conformations over- or under-represented in PPIs is a useful thing.

    So this post concerns the building of the general peptide conformer library. I've looked at tetrapeptides in the first case - since each amino acid residue in a protein has an average molecular weight of just over 110 - this gives the average tetrapeptide a weight of about 440 - but the minima is for Gly-Gly-Gly-Gly (weight ~246 Da) and the largest is Trp-Trp-Trp-Trp (weight ~762 Da). So if we are thinking about historical drugs and in particular small rigid scaffolds, this tetrapeptide will be big enough.

    Part 2 after a sandwich.....