ChEMBL

Finding Redox Pairs of Compounds

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. 

George

Meeting up at the ACS in New Orleans

"I am not a number, I am a free man" - but I do have an ORCID ID!

Paper: Brain: Biomedical Knowledge Manipulation

%A S. Croset
%A J.P. Overington
%A D. Rebholz-Schuhman
%D 2013
%T Brain: Biomedical Knowledge Manipulation
%J Bioinformatics
%V 29
%O DOI:10.1093/bioinformatics/btt109
%O PMID:23505292

New Drug Approvals 2013 - Pt. IV - Ospemifene (OSPHENA®)

ATC Code: Not Assigned

Wikipedia: Ospemifene

On February 26, FDA approved Ospemifene (Trade Name: OSPHENA, PubChem: CID 3036505, ChEMBL: CHEMBL2105395, ChemSpider: 2300501) for the treatment of moderate to severe Dyspareunia - symptom of vulvular and vaginal atrophy due to menopause.

Dyspareunia, is pain during or after sexual intercourse. It can affect men, but is significantly more common in women, affecting up to one-fifth of women at some point in their lives. Women with dyspareunia may have pain in the vagina, clitoris or labia. This may be due to medical or psychological causes. There are numerous medical causes of Dyspareunia, like : Vaginismus, Pelvic Inflammatory Disease, Genital or Pelvic Tumors, Urethritis, Urinary Tract Infection, Vaginal Atrophy, Vaginal Dryness, Vulvar Cancer, Childbirth Trauma (postpartum), Skin Conditions (Lichen Sclerosus, Lichen Planus, Eczema, Psoriasis), Female Genital Mutilation, Endometriosis  - many of which can be treatable.

Ospemifene is a novel selective estrogen receptor modulator (SERM) - class of compounds that acts on Estrogen Receptors (ER's). SERM's has a distinguishing characteristic that makes them different from pure receptor agonists and antagonists, which is - that their mode of action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues (Pub-Med). Ospemifene is an Estrogen agonist/antagonist with tissue selective effects. Its biological actions are mediated through binding to Estrogen Receptors (Short Name: ER, ESR; UniProt: Q92731 and P03372; ChEMBL: CHEMBL2093866). This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).

Mechanism of action of SERM's is of mixed agonism/antagonism which may differ depending on the chemical structure, but, for at least for some SERM's, it appears to be related to -

1. The ratio of co-activator to co-repressor proteins in different cell types.

2. The conformation of the estrogen receptor induced by drug binding, which in turn determines how strongly the drug/receptor complex recruits co-activators (resulting in an agonist response) relative to co-repressors (resulting in antagonism).

The protein sequences of human ER-alpha (ESR1) and ER-beta (ESR2) can be downloaded in fasta format from the link here. (courtesy UniProt)

Compound Name : Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol

Canonical SMILES : OCCOc1ccc(cc1)\C(=C(\CCCl)/c2ccccc2)\c3ccccc3

Standard InChI : InChI=1S/C24H23ClO2/c25-16-15-23(19-7-3-1-4-8-19)24(20-9-5-2-6-10-20)21-11-13-22(14-12-21)27-18-17-26/h1-14,26H,15-18H2/b24-23-

Standard InChI Key : LUMKNAVTFCDUIE-VHXPQNKSSA-N

Ospemifene, an ER agonist/antagonist, has a molecular weight of 378.9. The recommended dosage is 60 mg, available in the form of table for oral administration. After single dosage of Ospemifene under fasted conditions, mean Cmax and AUC (0 to infinity) were 533 ng/mL and 4165 ng.hr/mL, respectively. With a high fat/high diet, mean Cmax and AUC (0 to infinity) were 1198 ng/mL and 7521 ng.hr/mL, respectively. It is highly bound to serum proteins ( >99%) with apparent volume of distribution of 448 L. Ospemifene primarily undergoes metabolism via CYP3A4, CYP2C9 and CYP2C19 and the major metabolite was 4-hydroxyospemifene. Clearance of ospemifene was 9.16 L/hr and terminal half-life was 26 hrs. Following an oral administration of ospemifene, approximately 75% and 7% of the dose was excreted in feces and urine, respectively.

Osphena comes with a boxed warning in the form of Endometrial Cancer and Cardiovascular Disorders. Since Ospemifene is an ER agonist/antagonist with tissue selective effects. In endometrium, due to Ospemifene agonistic effects, there is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. There is a reported increased risk of stroke and deep vein thrombosis in postmenopausal women who received daily oral conjugated estrogens alone therapy over 7.1 years. So, Ospemifene should be prescribed for the shortest duration consistent with treatment goals.

Full prescribing information can be found here.

The license holder is Shionogi Inc., and the product website is www.osphena.com.

How do you find ChEMBL-like papers in PubMed?

If only....

Here at ChEMBL Towers, we appreciate the delight that comes with computationally solving problems, in particular those that would otherwise be a tedious manual task - the world would be perfect if we could somehow automate and expand the search for med chem SAR literature to be included in ChEMBL by some sort of classification mechanism that distinguishes between 'ChEMBL-like papers'  and 'other literature' ...

As it turns out, this type of classification problem is already addressed in other fields and is generally known as text mining. It should come as no surprise that text mining was the internal trend of the month - last month. Text mining has a lot of potential for us in ChEMBL. Possible application areas include: patent text-mining, drug repurposing, and even assay auto extraction and curation. Text mining techniques have previously been applied for in many fields, including sentiment analysis, social media mining etc.

Why not?...

However, in order to tune the text mining song to our needs we decided to input some tricks from cheminformatics. The initial goal of our exercise was to create a reliable classification measure to separate 'interesting' ChEMBL papers from the rest. To this end we started with the full set of paper abstracts that are included in ChEMBL_15 (about 45,000 papers), this was our set of actives (chembl-like). In order to discriminate against another type of papers we also compiled a random subset (again about 45,000) retrieved from MedLine, this was our set of inactives (background). To capture this information we applied the Bag-of-Words (BoW) method which was constructed from both abstracts and titles.

1. From the abstracts and titles punctuation and non-alphanumeric characters were removed

2. The abstracts and titles were split on spaces and all words were placed in an array

3. From this array uni-grams, bi-grams and tri-grams were created (eg. 'SAR', 'structure-activity relationship' or 'series was synthesized' ).

4. From the n-grams stopwords were removed if they formed the majority of the n-gram.

Now the sets looked like this graphically if we create a nice word cloud (ChEMBL on the left and medline on the right, previously posted by JPO - since he steals all our good stuff, and pretends it is his).

As this method quickly leads to a very large collection of possibly not so relevant words we decided to perform Bayesian feature selection. Hence the n-grams were placed in a large array and a Bayesian classifier was used to select 128 relevant n-grams (...yes we also tried 64, 256, 768, 999 or all...) that were relevant to model the classes. Keeping to chemoinformatics traditions the selected n-grams were converted into a counts-string which was used as a descriptor for each paper (...yes, we also tried bits... ).

Subsequently, the collections of bitstrings were fed into a random forest (RF) classifier (shown in our hands to outperform a Bayesian method) that was used to train a classifier. We used both out-of-bag validation and external validation (50 % training - 50 % validation). Now the nice thing about doing this with RFs is that you can see what features (in this case words) are important to distinguish ('W__' and '__' can be ignored, you'll note that we need to do some stemming too!). It seems 'compounds' is essential...

As it turns out that this type of classifier performs rather well on the very homogenous set that makes up ChEMBL. Our models consistently achieved a sensitivity of 0.91 an specificity of about 0.94 with MCC about 0.85.

So let's make it more interesting...

So now that we have this method we can try some interesting exercises. We decided to train a model on ChEMBL-10 and use that to try and predict if the papers included exclusively in release 15 would be correctly classified, and in fact it did, but with a little lower accuracy (Sensitivity 0.81, specificity 0.94 and MCC 0.76). So this would mean that, while the method works, these models are not perfect.

However, we have previously decided to abstract from a relatively small set of SAR data rich journals, and have maintained this selection over time, so this result is no big deal. The real proof of concept however is a validation on completely different papers. Those that our not part of the normal ChEMBL body but might still contain interesting information to be abstracted. Here we used a set of papers (556) that have been included in BindingDB but are not in ChEMBL. The goal is to see what fraction of papers is actually retrieved by our text mining model. In total 513 of the 550 are actually flagged as ChEMBL-like (corresponding to a sensitivity of about 0.92).

However, the results should still be taken with caution, as the majority of the ChEMBL papers are from J. Med. Chem. (A) and Bioorg. Med. Chem. Lett. (B). These display a different profile than for instance the papers from J. Nat. Prod. (C, see below for the 10 top words for each of these). Still the term 'compounds' appears in all (and was also essential in our model further up). But this also points to opportunities to develop similar pipelines, sitting off PubMed updates looking for Natural Product bioactivity containing literature.

In conclusion...

In summary, we are very happy with this approach to document classification as it significantly increases our productivity. Currently this a approach is applied in our in house curation interface (more on this in the future, but it is cool), an ongoing project of Rita Santos (more on this later, but it is cool), and the identification of protein-family-like (e.g. GPCR-related) publications.

If you think this is interesting work please get in touch! We would be more than happy to share the PP protocols / KNIME workflows developed in house and more of our experiences doing this exercise.

Gerard & George

The results are in - inorganics are out!