• New Drug Approvals 2011 - Pt. XV Rilpivirine (EdurantTM)





    ATC code (partial): J05AG

    On May 20th, the FDA approved Rilpivirine (Tradename: Edurant; Research Code: TMC-278, NDA 202022), an HIV-1 Non-nucleoside reverse transcriptase inhibitor (NNRTI), for the treatment of HIV infection in treatment naive patients in combination with other HIV therapies. HIV infection is a serious, and if untreated fatal infection caused by a lentivirus, however due to intensive research, leading to a wide variety of antiviral agents the disease is treatable with a substantial increase in quality of life anticipatable.

    Rilpivirine is an inhibitor of the essential reverse transcriptase (RT) enzyme of HIV-1. (ChEMBLID:CHEMBL247; Uniprot ID:Q72547), a viral protein required for the transcription of the single-stranded RNA genome of HIV-1 into double-stranded DNA - this is the opposite of the classical transcription of DNA into RNA. The RT enzyme is translated as part of a long complex gag-pol polyprotein, and requires specific proteolytic cleavage by a virally encoded protease (HIV-1 PR) - this protease is also the target of many successful HIV therapies. There are two distinct binding sites within the RT enzyme that are therapeutically targetable - first is the catalytic center for drugs such as AZT and other nucleoside analogues, the second is the 'allosteric' non-nucleoside site, which is only usefully present in the HIV-1 RT sequence, and so NNRTI agents are usually specific for HIV-1. Rilpivirine is a non-competitive inhibitor of HIV-1 RT.

    There are many protein structures known for RT in complex with inhibitors, including that of the complex with TMC-278/rilpivirine itself - PDBe:3mee. The RT enzyme has an interesting composition, being a heterodimer of two proteins derived from the same gag-pol polyprotein - one called p66, the other p51, both contain the polymerase functionality (the polymerase domain is composed of four structural subunits, within each polymerase unit, these domains are arranged differently forming an asymmetric dimer), the p66 additionally contains a further catalytic function - Ribonuclease H.




    There are a number of other approved NNRTIs, and a large number in either current or stalled clinical development. Approved drugs include the USANs Efivarenz, Nevirapine, Delaviridine & Etravirine.




    Rilpivirine (IUPAC:4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile; SMILES: CC1=CC(=CC(=C1NC2=NC(=NC=C2)NC3=CC=C(C=C3)C#N)C)C=CC#N
    PubChem:6451164) is an achiral synthetic small molecule drug, it is a member of the diaryl pyrimidine (DAPY) class of NNRTIs. It has a molecular weight of 366.4 Da, contains 2 hydrogen bond donors, 4 hydrogen bond acceptors, and has a LogP of 4.5.

    Rilpivirine is available as oral tablets contains 27.5 mg of Rilpivirine hydrochloride (equivalent to 25 mg of active ingredient). Rilpivirine should be administered with food, since in fasted patients, absorption is significantly lower. Human plasma protein binding (ppb) primarily to serum albumin is approximately 99.7%. The primary metabolising route of Rilpivirine is through oxidative metabolism by CYP3A4, with a half-life of ca. 50 hr, with elimination being largely via feces.

    The license holder for Rilpivirine is Johnson & Johnson., and the full prescribing information can be found here.

  • Recruitment: Senior Data Curator, IUPHAR Database, Edinburgh


    Here is a job advert, not for a ChEMBL position, but as part of the (fabulous) IUPHAR-DB project.

    Senior data curator to assist with the development of the IUPHAR Database (http://www.iuphar-db.org) and the British Pharmacological Society Guide to Receptors and Channels (http://www.brjpharmacol.org/view/0/GRAC.html). You should hold a PhD or equivalent in Pharmacology, Medicinal Chemistry or a related discipline together with relevant experience in bioinformatics or chemoinformatics. Based in the Queen's Medical Research Institute, you will work independently on a day-to-day basis but in close contact with Professor Tony Harmar, with the database developer and in liaison with IUPHAR and BPS. Closing date is 22nd June.

    For further information and to apply, click here (see http://bit.ly/kDl7mu)

    This post is fixed term until 31st July 2012 with possibility of extension should further funding be obtained.

  • pychembl: ChEMBLdb pythonified using SQLAlchemy


    A simple cross post from the /chemical/structure Blog - the guys have done a great job of setting up a python queryable version of the ChEMBL data.

    Here's the link!

  • Conference: New Perspectives on Transporters in Drug Discovery and Development: ADME and Beyond, 23rd June 2011, London


    The Society of Medicines Research (SMR) have a great conference on Transporters in Drug Discovery , being held on Thursday 23rd June 2011, at the Millennium Gloucester Hotel, Kensington, London.

    Further details are on the SMR website. I (jpo) will actually manage to attend this one, so if anyone wants to meet up, that would be great.

  • Publication: Chemogenomics Approaches for Receptor Deorphanization and Extensions of the Chemogenomics Concept to Phenotypic Space


    A paper has recently been published, which may be of interest; it covers the use of chemogenomics class data in activities such as target prediction, receptor deorphanisation and so forth. A link the the paper is here.


    %T Chemogenomics Approaches for Receptor Deorphanization and Extensions of the Chemogenomics Concept to Phenotypic Space
%J Curr. Topics Med. Chem.
%V 11
%A E. van der Horst
%A J.E. Peironcely
%A G.J.P. van Westen
%A O.O. van den Hoven
%A W.R.J.D. Galloway
%A D.R. Spring
%A J.K. Wegner
%A H.W.T. van Vlijmen
%A A.P. IJzerman
%A John P. Overington
%A A. Bender
%D 2011

  • ChEMBL schema walkthrough webinar - 1st june

    Sign up If you are I interested. Details are here

  • More GPCR structures...


    Some more structures of a GPCR are available - for the Adenosine A2A receptor complexed to the endogenous ligand adenosine (PDBe:2YDO), and also a further complex with the adenosine analogue NECA (N-ethyl-5'-carboxyamido adenosine) (PDB:2YDV). These structures add significantly to our understanding of the mechanism and structural aspects of agonist signalling.


    adenosine


    %T Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation
%A G. Lebon
%A T. Warne
%A P.C. Edwards
%A K. Bennett
%A C.J. Langmead
%A A.G.W. Leslie
%A C.G. Tate
%J Nature
%D 2011
%O doi:10.1038/nature10136

    Update: I've also updated the joy annotated alignment with the new structures (and fixed the ordering to something more usable).

  • ChEMBL Cookies

    On the 26th May 2011 new European regulations will come into force, which are aimed at providing website users with a better understanding of data being collected when they visit a website. Covered under these regulations, is the use of cookies, which are small pieces of of text set by some websites and can be used for authentication, saving site preferences/shopping cart selections and storing session information. In short, the cookie is being used to get around the inherently stateless nature of HTTP.

    There is currently a bit of confusion over what the final regulations and national implementations will be, so the Information Commissioner’s Office (ICO) has drawn up some guidelines, however these will not be finalised until after 26th May 2011 :(. In preparation for these changes we thought we would list the cookies which might be set when a user visits the the ChEMBL interface:

    Cookie NameDetails
    ci_sessionGenerated by Codeignitor  web application framework and used to store session information for each user
    chembl_sketcherStores user selected compound sketcher on https://www.ebi.ac.uk/chembldb/index.php/compound page
    marvin, jme, jdrawStores sketched structure on https://www.ebi.ac.uk/chembldb/index.php/compound page. Cookie is used for each sketcher as different formats are used to store structure.
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