An old colleague of mine Bob Sheridan has just published an interesting (and pretty comprehensive) paper in JCIM, Debunking the Idea that Ligand Efficiency Indices are Superior to pIC50 as QSAR Activties.
There seems to be a proliferation of various ligand efficiency (LE) metrics intended to give the scientist an objective measure of how efficiently a molecule is binding to the intended target Ligand efficiency: a useful metric for lead selection. Whilst I’ve always found them useful to get a feel for comparing the influence of substituent changes in QSAR studies, for example introduction of a large lipophilic substituent may buy affinity but at the expense of LogP. I do wonder at times if the LE numbers are assuming greater importance than the underlying biological data.
Recently several papers have use LE instead of pIC50 in QSAR models and claimed improvements, this seems a little counterintuitive and Bob Sheridan very nicely offers an explanation.
The apparent superiority is a statistical artefact and the improvement occurs when.
Ligand efficiency indices are highly correlated with the physical property included in their definition (number of non-hydrogens, ALOGP, TPSA, etc.),
The property is easier to predict than the original pIC50.
What is Wellcome Open Research?
- A platform for Wellcome-funded researchers to rapidly publish any research outputs they wish to share.
- Supports reproducibility and transparency.
- Uses an open research publishing model: immediate publication followed by open invited peer review.
- Includes all supporting data, enabling reanalysis, replication and reuse.
A collection of 47 deprioritised pharmaceutical compounds and up to £5 million is being made available to academic researchers through the latest round of the MRC-Industry Asset Sharing Initiative. The collaboration, between the MRC and six global drug companies, is the largest of its kind in the world.
The list of compounds is available here together with brief description of the molecular target and pharmacology, Safety, Tolerability and toxicity information, and any clinical studies that might have been undertaken.
The latest newsletter from the European Lead Factory has just been published and highlights a number of notable achievements.
As a result of the screening campaigns >3000 qualified hits have been awarded to private and public target owners. 72 public target programmes have been accepted, 48 high throughput screens finished and 41 hit lists with associated data reports handed over to the target owners. >150 bespoke assays have been developed in order to extract the most interesting hits for public programmes.
There are now 450,000 compounds in the compound library of which 120,000 are novel compound specifically synthesised for the ELF.
You can read more details here https://www.europeanleadfactory.eu/results/
The European Lead Factory is a collaborative public-private partnership aiming to deliver innovative drug discovery starting points. Having established the first European Compound Library and the first European Screening Centre, the EU Lead Factory aims to give free access to up to 500,000 novel compounds, a unique industry-standard uHTS platform, and much more.
We are now starting to see publications describing these endeavours..
ChEMBL 22 has been released. ChEMBL is a database of bioactive drug-like small molecules, it contains 2-D structures, calculated properties (e.g. logP, Molecular Weight, Lipinski Parameters, etc.) and abstracted bioactivities (e.g. binding constants, pharmacology and ADMET data).
This version of the database, prepared on 8th August 2016 contains:
- 2,043,051 compound records
- 1,686,695 compounds (of which 1,678,393 have mol files)
- 14,371,219 activities
- 1,246,132 assays
- 11,224 targets
- 65,213 documents
There is more information in the ChEMBL blog post
Still a few places left at the Cheminformatics for Drug Design: Data, Models & Tools meeting organised by SCI's Fine Chemicals Group and RSC's Chemical Information and Computer Applications Group has been extended.
Imperial War Museum, Duxford, UK Wednesday 12 October 2016
Full details are available here https://www.soci.org/Events/Display-Event?EventCode=FCHEM481
Sounds an excellent meeting and you will have a chance to look around the aircraft at the Duxford Imperial War Museum.
The European Lead Factory started work just over 3 years ago and have just released an update on results to date.
The EU Lead Factory is an IMI-funded project that aims to create new chemistry based on crowd-sourced ideas and boost applicants’ drug discovery programmes at no upfront costs
- A Sweden-based start-up company, ScandiCure AB, has been founded based on the results of an EU Lead Factory target programme. ScandiCure is developed with the support and investment of GU Ventures, which is wholly owned by the Swedish State.
- Patents on EU Lead Factory compounds for treatment of multi-resistant bacteria infections and cancer.
- An EU Lead Factory programme accepted by IMI’s ENABLE for preclinical development.
- In vivo proof-of-concept generated with EU Lead Factory compounds.
- 2 PhD thesis enhanced with EU Lead Factory target programme assay development and screening results.
- >35 scientific, peer-reviewed articles, whereof one is the 4th most downloaded article published in Drug Discovery Today in 2015.
- 450,000 compounds in the Joint European Compound Library (JECL), whereof >120,000 of the prospected 200,000 novel screening compounds have been synthesised. 330,000 compounds were selected and assembled from the EFPIA participants’ proprietary compound collections within 6 months of operation.
- Many testimonials of the high quality of the EU Lead Factory output and the JECL compounds. For example, 17/49 EFPIA partner screens have triggered further work.
- 72 public target programmes accepted, 48 high throughput screens finished and 41 hit lists with associated data reports handed over to the target owners.
- In total, 2925 qualified hits have been granted public and private target owners (1041 and 1884, respectively).
- >1500 bespoke compounds synthesised in hit validation and hit-to-lead phase of public target programmes.
- >10 crystal structures of target–compound complexes have been solved.
- >150 bespoke assays have been developed in order to extract the most interesting hits for public programmes.
- 12/14 of the public target programmes offered to the industry EFPIA participants have been asked to provide a dossier for further assessment.
- >30 academic postdoctoral fellows trained in industry methods and approaches.
- Researchers in 13 countries (BE, DE, DK, ES , FR , IT, IL, HU, NL, PL , PT , SE, UK) involved. Partners spread over 8 countries and target owners over 11.
- 2 Custom-built data management platforms, the Honest Data Broker system developed to enable screening data management and triaging, whilst ensuring confidentiality and patentability; TarosGate2, a chemistry workflow management system with a secure built-in electronic laboratory notebook.
I’ve been involved in a number of screens and we have been very happy with the results, this is a great resource long may it continue.
It is also worth noting that the next submission deadline is 10th October 2016, here is the link for submitting assays for consideration. https://www.europeanleadfactory.eu/how-to-submit/drug-target-assays/
|Event||FBLD 2016 (Fragment-based Lead Discovery Conference 2016)|
|Place||Cambridge, Massachusetts, USA|
|Dates||9th-12th October 2016|
|Poster abstracts||Closing date is 30th September|
|Event||Fragments 2017 - 6th RSC-BMCS Fragment-based Drug Discovery meeting|
|Dates||Sunday to Tuesday, 5th to 7th March 2017|
|Place||Parkhotel Schönbrunn, Vienna, Austria|
I’ve just updated the page on molecular interactions, expanding the section on halogen bonding interactions.
I’ve just updated the page on solubility and added a couple of useful assay references.
Solubility may also have an impact on preclinical assays, limited solubility in preclinical ADMET assays may give a false impression of the compounds profile in in vitro assays. Many of the false positives seen in Fragment-based screening are thought to be due to poor solubility at the high concentrations used in the screen. Perhaps the most important is the impact poor solubility can have on gastrointestinal absorption it may also preclude other routes of administration (intravenous).