ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Friday, 26 April 2013

PubMed Watcher - Tailored biomedical literature feed

Following the scientific literature is a difficult task, it's not something you can do lying on the beach. Among the huge number of articles that are published every day only a few really matter to you. These are the articles you are going to have the time to read and that are relevant to your research.

In order to spot the relevant papers, there are a number of thematic approaches. For example, most journals publish articles in a relatively restricted field - and so a scientist can follow a thematic journal (like PLOS, Nature Biotechnology, etc). But then you'll still receive a lot of information to be sorted and you will obviously notice only the recent work. Maybe that interesting article you are waiting for has been published 5 years ago and you will then never ever notice it that way.

You can also keep track of literature with a keywords search (that you save somehow). This approach presents some problems too: What keywords should you search for? Your research is certainly more complex and subtle than "cancer p53" or "sequence analysis".

PubMed Watcher is an experimental tool designed to help biomedical scientists to read efficiently adequate literature. The tool is built based on the following assumptions:
  • Relevant papers are forever: PubMed Watcher abstracts away from the publishing date.
  • Relevant papers are everywhere: The tool considers all the articles indexed by PubMed.
  • Your research cannot be defined by a few keywords only: PubMed Watcher relies on Key Articles as a means to express the science you care about.
More details and the methodology behind the tool is presented here alongside an example to illustrate how it works.

PubMed Watcher is still in beta testing, please submit your feedback or idea for improvements here or directly by email.


Wednesday, 17 April 2013

2nd RDKit UGM, 2-4 October 2013

We are very happy to announce the 2nd RDKit User Group Meeting. The meeting will take place October 2nd-4th here the Genome Campus in Hinxton, UK. We're using a different format for the meeting this year:

Days 1 and 2: Talks, lightning talks, roundtable(s), discussion, and something new: talktorials! Talktorials are somewhere between a talk and a tutorial, they cover something interesting done with the RDKit and include the code used to do the work. During the presentation you'll give an overview of what you did and also show the pieces of the code that are central to the work. The idea is to mix the science up with the tutorial aspects.

Day 3 will be the first ever RDKit sprint: those who choose to stay will spend an intense day working in small groups to produce useful artifacts: new bits of code, knime nodes, knime workflows, tutorials, documentation, IPython notebooks, etc. We'll see who's there and what folks are interested in contributing and go from there.

There will also be, of course, social and networking activities!

Registration is free at the following link:

We are now looking for people who are willing to do presentations or talktorials on the first two days. If you're interested in contributing, please send us an email. Lightning talks don't need to be arranged too far in advance; we'll start collecting the list of people interested in doing those shortly before the event.

We are really looking forward to seeing a bunch of you again, to meet some new people from the ever growing RDKit developer and user community, and to hear some more cool stories about what people do with the RDKit.

Greg and George

Tuesday, 16 April 2013

New Drug Approvals 2013 - Pt. V - Canagliflozin (INVOKANA™)

ATC Code: A10BX (incomplete)
Wikipedia: Canagliflozin

On March 29th the FDA approved Canagliflozin (trade name INVOKANA™) to improve glycemic control for the treatment of diabetes type 2. Canagliflozin is to be used in combination with proper diet and exercise. Canagliflozin is a subtype 2 sodium-glucose transport protein (SGLT2, ChEMBL3884) inhibitor. Canagliflozin is a first-in-class drug with several others still in clinical trials

SGLT2 is found in the proximal tubule of the nephron in the kidneys (as is paralog SGLT1, ChEMBL4979). SGLT2 one of the 5 known members of the sodium-glucose transporter proteins family. The transporter is responsible for 90 % of the total renal glucose reuptake (corresponding to 98 % of the uptake in the proximal convoluted tubule). The protein has a relatively low affinity for glucose compared to SGLT1 (2 mM versus 0.4 mM) but a higher capacity. Hence inhibition of this protein leads to a lowering of the glucose plasma concentration. SGLT2 is a 672 amino acid protein which can be found on Uniprot (P31639). The most similar PDB structure is the sodium/glucose costransporter from Vibrio parahaemolyticus (3DH4). 

The paralog SGLT1 (664 amino acids, 57.63% identical to SGLT2) is also found in the intestine where it is responsible for glucose uptake. Hence SGLT1 forms an important anti-target for Canagliflozin. 

Canagliflozin (CHEMBL2048484 ; Chemspider : 26333259 ;  Pubchem : 125299338 ; Unichem Identifier 1075025) is a small molecule drug with a molecular weight of 444.5 Da, an AlogP of 3.45, 5 rotatable bonds and does not violate the rule of 5.

Canonical SMILES : Cc1ccc(cc1Cc2ccc(s2)c3ccc(F)cc3)[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O

InChi: InChI=1S/C24H25FO5S/c1-13-2-3-15(24-23(29)22(28)21(27)19(12-26)30-24)10-16(13)11-18-8-9-20(31-18)14-4-6-17(25)7-5-14/h2-10,19,21-24,26-29H,11-12H2,1H3/t19-,21-,22+,23-,24+/m1/s1

Canagliflozin is contra-indicated when there is a history of serious hypersensitivity reactions to Canagliflozin or in cases of severe renal impairment, ESRD, or on dialysis.

The recommended starting dose of Canagliflozin is 100 mg once daily, taken before the first meal of the day. The dose can be increased to 300 mg once daily in patients tolerating Canagliflozin. 100 mg should be dosed once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control. Canagliflozin is limited to 100 mg once daily in patients who have an eGFR of 45 to less than 60 mL/min/1.73 m2.Canagliflozin should be discontinued if eGFR falls below 45 mL/min/1.73 m2.

O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.

Following administration of a single oral [14C]canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2%  of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible. Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min. Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.

The license holder is Janssen Pharmaceuticals, Inc. and the full prescribing information can be found here.

Book - An introduction to Medicinal Chemistry

There is a new edition of the great med. chem. book "Introduction to Medicinal Chemistry" by Graham Patrick out - I picked up a copy at the Oxford University Press stand at the ACS, and am now flicking through it recovering from the flight from Miami.

Here's a link to the book at Amazon (UK store).

%A G. L. Patrick
%T An Introduction To Medicinal Chemistry
%D 2013
%I Oxford University Press
%O 5th Edition
%O ISBN: 978-0-19-969739-7

I worked on some new slides while away, and I think there are a few interesting things to blog about over the next few weeks.

Thursday, 4 April 2013

ChEMBL iPad App from Dotmatics in the iTunes Store

A local SME - Dotmatics - has created a really cool iPad app containing all of ChEMBL 15 in chemically searchable form - chemical structure and property data is local to the iPad, and bioactivity data is then retrieved over the web for selected compounds. Here's a link to details of the app.

New kinase inhibition full matrix dataset

We've just processed and integrated a new full matrix kinase inhibition dataset, kindly provided by EMD Millipore. As described in this recent paper, it covers 234 human wildtype kinases and kinase complexes, as well as 158 'standard' kinase inhibitors tested at two concentrations, leading to more than 73,000 data points. Analysis of the data could provide new insights to kinase selectivity/promiscuity/polypharmacology (depends on how you look at it) and their relationship with chemical structure. The dataset will be available with ChEMBL_16 next month. 

PS: The image above shows the activity profile of four kinase inhibitors across the human kinome families from the Millipore data. It was produced with circos by Rita.