ChEMBL

Many of the readers of the ChEMBL-og are interested in drug discovery against neglected and rare diseases. One of the great things for us in this field is the opening up of data in this field - there was the almost simultaneous release of primary HTS data from GSK, Novartis & St. Judes in 2011, more recently the results of a GSK HTS for TB. Having this data publicly available, for all, means that many smart people can analyse the data, and of course, pooling data in this way effectively is equivalent to running the assay against a far larger compound set, and allows more powerful cheminformatics analysis to identify chemical series, preliminary SAR, etc. Many of these datasets are available in our ChEMBL-NTD and ChEMBL-Malaria archives - and we know 2013 will be a great year for more data just like this! All these data are available for download, in the exact form as supplied by the depositor, no accounts/passwords, no lock-in to a software infrastructure, with no restrictions - just as it should be. Free the Data to set the World Free of Disease!

One of our partners, Medicine for Malaria Ventures (MMV) have recently announced an opportunity to get some real funding to take this data forward to real drugs. Further details of the call are here.

The deadline for applications is 12 noon CET March 15th,

ATC Code:

Wikipedia: Raxibacumab

On December 14th 2012 the FDA approved Raxibacumab for the treatment of inhalation anthrax, a form of anthrax caused by the inhalation of anthrax spores. The drug is also approved to treat inhalation anthrax when alternative therapies are not available or appropriate. Raxibacumab is a 146 kDa monoclonal antibody that is designed to neutralize the toxin secreted by Bacillus Anthracis. The FDA granted raxibacumab fast track designation, priority review, and orphan product designation.

Bacillus Anthracis toxin (Anthrax toxin) is a secreted three protein exotoxin. It consists of two enzyme components; lethal factor (LF, PDB 1PWU), a bacterial endopeptidase and edema factor (EF, PDB 1PWW), a bacterial adenylate cyclase. These are combined with one cell-binding protein; protective antigen (PA, PDB 1ACC). The individual components are non toxic and the combination of the enzyme components with the cell-binding protein makes them toxic. PA, in the form of a 83kDa protein, binds to the Anthrax Toxin receptor. Upon binding a 20kDa fragment is cleaved of the protein. The remaining protein (PA63) self assembles into a ring shaped oligomer. This oligomer acts as a pore precursor through which the enzymatic components enter the cell. EF, an 88kDa protein, acts as a Ca2+ and calmodulin dependant adenylate cyclase, raising cAMP levels (up to 200 fold in CHO cells) and disturbing water homeostasis in the cell. In turn disturbing signaling pathways and immune function. LF,  an 89kDa protein, is a Zn2+ dependant endopeptidase. The protein cleaves mitogen-activated proten kinase kinases (MAPKKs). This leads to altered signalling pathways and apoptosis. 

(Image adapted from http://www.kesimpulan.com)

Raxibacumab, efficacy has not been tested in humans but instead in monkey's and rabbit's for ethical reasons. Safety trials were conducted in 326 healthy human volunteers.  

Raxibacumab is available as a single-use vial which contains 1700 mg/34 mL (50 mg/mL) raxibacumab injection. Raxibacumab is administered as a single dose of 40 mg/kg intravenously over 2 hours and 15 minutes after dilution in 0.9% Sodium Chloride Injection, USP (normal saline) to a final volume of 250 mL. 

The PK of raxibacumab are linear over the dose range of 1 to 40 mg/kg following single IV dosing in humans. Following single IV administration of raxibacumab 40 mg/kg in healthy, male and female human subjects, the mean Cmax  and AUCinf were 1020.3 ± 140.6 mcg/mL and 15845.8 ± 4333.5 mcg·day/mL, respectively. Mean raxibacumab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution. Clearance values were much smaller than the glomerular filtration rate indicating that there is virtually no renal clearance of raxibacumab. 

The license holder is GlaxoSmithKline and the prescribing information can be found here.

ATC Code: J04AK05
Wikipedia: Bedaquiline

On December 28, the FDA approved Bedaquiline (as the fumarate salt; tradename: Sirturo; Research Code: R-403323 (for Bedaquiline Fumarate), R-207910 and TMC-207 (for Bedaquiline)), a novel, first-in-class diarylquinoline antimycobacterial drug indicated for the treatment of pulmonary multi-drug resistant tuberculosis (MDR-TB) as part of combination therapy in adults.

Turbeculosis is an infectious disease caused by the mycobacteria Mycobacterium tuberculosis, which usually affects the lungs. MDR-TB occurs when M. tuberculosis becomes resistant to the two most powerful first-line treatment anti-TB drugs, Isoniazid (ChEMBL: CHEMBL64) and Rifampin (ChEMBL: CHEMBL374478). Bedaquiline is the first anti-TB drug that works by inhibiting mycobacterial adenosine 5'-triphosphate (ATP) synthase (for Uniprot_IDs, clique here), an enzyme essential for the replication of the mycobacteria.

ATP is the most commonly used energy currency of cells for most organisms. ATP synthase produces ATP from adenosine phosphate (ADP) and inorganic phosphate using energy from a transmembrane proton-motive force generated by respiration. The image above depicts a model of the mycobacterial ATP synthase. ATP synthase has two major structural domains, F0 and F1, that act as a biological rotary motor. The F1 domain is composed of subunits α₃ (Uniprot: P63673), β₃ (Uniprot: P63677), γ₃ (Uniprot: P63671), δ and ε (Uniprot: P63662); the F0 domain includes one a subunit (Uniprot: P63654), two b subunits (Uniprot: P63656) and 9 to 12 c subunits (Uniprot: P63691) arranged in a symmetrical disk. The F0 and F1 domains are linked by central stalks (subunits γ and ε) and peripheral stalks (subunits b and δ). The proton-motive force fuels the rotation of the transmembrane disk and the central stalk, which in turn modulates the nucleotide affinity in the catalytic β subunit, leading to the production of ATP.

It has been shown that mutation in the atpE gene, which encodes the c subunit, of the mycobacterial ATP synthase, confers resistant to Bedaquiline, suggesting that Bedaquiline binds crucially to this target (although almost certainly other components of the complex are required for a competent binding site), inhibiting the proton pump of M. tuberculosis and therefore interfering with the rotation properties of the transmembrane disk, leading to ATP depletion.

>ATPL_MYCTU ATP synthase subunit c
MDPTIAAGALIGGGLIMAGGAIGAGIGDGVAGNALISGVARQPEAQGRLFTPFFITVGLV
EAAYFINLAFMALFVFATPVK

Another notable feature is the high specificity of Bedaquiline for mycobacteria. This is due to the fact that there is very limited sequence similarity between the mycobacterial and human atpE proteins.

Bedaquiline is a diarylquinoline antimycobacterial drug, which displays both planar hydrophobic moieties and hydrogen-bonding acceptor and donor groups. It has a molecular weight of 555.50 Da (671.58 for the fumarate salt), an ALogP of 6.93, 4 hydrogen-bond acceptors and 1 hydrogen-bond donor, and therefore not fully rule-of-five compliant.

Name: (1R, 2S)-1-(6-bromo-2­ methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol
Canonical Smiles: COc1nc2ccc(Br)cc2cc1[C@@H](c3ccccc3)[C@@](O)(CCN(C)C)c4cccc5ccccc45
InChI: InChI=1S/C32H31BrN2O2/c1-35(2)19-18-32(36,28-15-9-13-22-10-7-8-14-26(22)28)30(23-11-5-4-6-12-23)27-21-24-20-25(33)16-17-29(24)34-31(27)37-3/h4-17,20-21,30,36H,18-19H2,1-3H3/t30-,32-/m1/s1

The recommended dosage of Bedaquiline is 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks with food.

Bedaquiline shows a volume of distribution of approximately 164 L and a plasma binding protein of > 99.9%. Bedaquiline is primarily subjected to oxidative metabolism by CYP3A4 leading to the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6 times less active in terms of antimycobacterial potency. It is mainly eliminated in feces and the mean terminal half-life T_1/2 of Bedaquiline and M2 is approximately 5.5 months.

The license holder is Janssen Therapeutics and the full prescribing information of Bedaquiline can be found here.

Patricia

I must point out that this post has nothing to do with the smash-hit block-buster film Django Unchained from the superstar director Quentin Tarantino (but search engines may well be too stupid to realised this and bump the rank of this post).

Update: Voting is now closed.

jpo

jpo