Corporate Banner
Satellite Banner
Medicinal Chemistry
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Locating and Explaining ‘Activity Cliffs’ in SAR Datasets

Published: Monday, September 16, 2013
Last Updated: Monday, September 16, 2013
Bookmark and Share
Activity Miner from Cresset is an intuitive SAR interpretation tool, identifying key 3D structural and electrostatic changes that impact molecular activity.

In any dataset the extremes are usually the most interesting. For structure activity relationships (SAR) the attention-grabbing details are the small changes of structure or electrostatics that result in a large change of molecular activity; or the significant structural changes that have little or no impact on the activity.  

These are the nuggets of gold that can be mined from a SAR dataset, revealing valuable information about which structural elements affect a molecule’s biological activity, which areas of chemistry to explore next in a series and potentially which areas have as yet not been fully explored.

Rapidly identify activity cliffs
Cresset’s new Activity Miner is an intuitive interpretation tool designed to locate and explain the ‘activity cliffs’ in SAR datasets.  There has recently been a lot of interest, and many publications in the scientific literature regarding the identification and analysis of these activity cliffs, most often using 2D scaffold analysis to identify so-called Matched Molecular Pairs.  Uniquely, Activity Miner calculates and compares the 3D structural, shape and electrostatic changes between each pair of molecules in the dataset, enabling the detection and interpretation of the most important points in the SAR landscape.  

Activity Miner employs powerful visualization tools to make it easy to understand why a specific change resulted in improved activity.  When used to review project data, Activity Miner gives a valuable representation of all of the changes that have been made to a compound, and the resultant changes in activity.  When new data is incorporated, it can help the team to understand how the new data relates to the entire history of the project.  This helps researchers to spot meaningful relationships to old compounds that could otherwise be missed.activity_view_cresset.gif





The Activity View intuitively represents activity and structural similarity, making it easy to identify the changes that result in improved activity.  

The segments are green indicating a favourable shift in activity for most changes and all those that include a meta substituent.








3D electrostatic and shape similarities for more meaningful results
Activity Miner uses Cresset’s molecular fields so that 3D electrostatic and shape similarities and differences can be analyzed alongside 2D structural relationships.  Critically, these 3D comparisons give clear indications as to why a particular change is important for activity, and will complement 2D methods, in identifying key features. 

For example, changing a simple phenyl group into a difluorophenyl may impart significantly more activity.  2D comparisons of these molecules would rightly identify this relationship as important but would give no indication of why. However, when compared using 3D electrostatics it becomes clear that the fluorine atoms completely alter the electron density of the aromatic ring as well as introducing potential interactions to the target protein.  This knowledge clarifies the optimization strategy that should be followed in this region.

So far as we are aware, Activity Miner is the first commercially available tool that enables researchers to use 3D and 2D activity cliffs to mine structure activity relationships in an intelligent and intuitive way.

Powerful and intuitive visual interpretation of data
Activity Miner’s intuitive visualization makes it easy to identify interesting areas of a dataset.  The relationships between all molecules is displayed in a color-coded matrix, the changes that results in the highest activity cliffs are highlighted in the Top Pairs table view, or the innovative Activity View can be used to browse the SAR around a specific compound with changes in activity and similarity highlighted. 

The Activity View (illustrated above) focuses on one compound, surrounded by its most similar neighbours.  Strong colours indicate more significant changes in activity, while structural similarity is indicated by segment height.   The view acts as a browser: click a compound to compare it to the current focus compound; double click to make it the centre of the view. Navigation through the landscape or through the SAR of a set of related compounds becomes rapid and meaningful. 

Insights into the SAR for a recent set of PERK inhibitors using Activity Miner 
A recent report of a series of PERK inhibitors (J. Med. Chem 2012, 55, 7193) described extensive SAR. Using Activity Miner to study these compounds rapidly reveals important insights. The Activity View (shown above) around a para-fluorophenyl substituent shows in a simple graphic that substitution of this ring is strongly preferred in the meta-position over and above the para.  The segments are green indicating a favourable shift in activity for most changes and all those that include a meta substituent.

A second important part of the SAR is revealed by studying the effect of changes in the heteroaromatic scaffold. Critically, changing the Furanopyrimidine core with an N-methyl pyrrolopyrimidine gives >1 log unit improvement in activity. Examination of the electrostatics of these two compounds reveals the cause. Introduction of the N-Me unit changes both the dipole across the heteroaromatic ring and the electron density of the aromatic ring itself. A fact that can then be exploited in the design of new inhibitors.

Furanopyrimidine-core-compa.gif
Left: Furanopyrimidine core compared to Right: N-methyl pyrrolopyrimidine core showing raw electrostatic potentials (top) and the difference in the potentials (bottom). Negative regions are depicted in blue, positive regions in red. The more active pyrrolopyrimidine has a higher electron density in the aromatic ring shown by the large blue surface in the lower right picture.

Activity Miner is available as a feature of the following software products:

• Torch: Cresset’s 3D molecular design and SAR tool for medicinal chemists. Use it to take leaps in structural design while maintaining or improving biological activity.
• Forge: Cresset’s powerful computational suite for understanding SAR and molecular design. Forge gives you control and insight into your activity data, enabling you to plan the direction of your project with confidence.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Cresset Donates to Novartis’ TExts to Sub-Saharan Africa Project
Project donates textbooks to Kenyan university libraries.
Tuesday, September 30, 2014
CloudScientific Appointed as Cresset’s Distributor in China
CloudScientific appointed as distributor of computational chemistry software.
Friday, July 11, 2014
Victrix CMCC Chooses Cresset’s Software for Drug Discovery Consulting Projects
Cresset’s software will help Victrix clients to carry out structure based drug design projects.
Friday, June 28, 2013
Cresset Announces new International Sales Team
Cresset has expanded its computational chemistry software sales team in the U.S. and Europe.
Thursday, September 09, 2010
Cresset Announces Appointment of Rob Scoffin as new CEO
Rob replaces Beatrice Leigh, who will now become non-executive Chairman of the Board.
Monday, April 26, 2010
Cresset Expands Sales Pipeline Potential through CambridgeSoft Alliance
CambridgeSoft sells Cresset’s FieldAlign and FieldTemplater products using its direct, telesales and ecommerce channels.
Monday, April 20, 2009
Scientific News
Toxin from Salmonid Fish has Potential to Treat Cancer
Researchers from the University of Freiburg decode molecular mechanism of fish pathogen.
New Diabetes Drug has Unexpected Side Effect
A type of drug used to treat diabetes may reduce the risk of developing Parkinson’s disease, according to new research.
Researchers Develop Vaccine that Protects Primates Against Ebola
A collaborative team from The University of Texas Medical Branch at Galveston and the National Institutes of Health have developed an inhalable vaccine that protects primates against Ebola.
Cannabis May Be Used to Treat Fractures
TAU researcher finds non-psychotropic compound in marijuana can help heal bone fissures.
A Novel Drug to FIght Malaria
An international team of scientists has announced that a new compound to fight malaria is ready for human trials.
New Cell Structure Finding Might Lead to Novel Cancer Therapies
University of Warwick scientists in the U.K. say they have discovered a cell structure which could help researchers understand why some cancers develop.
Creating More Potent Vaccines
Yale researchers uncovered a new role for a type of immune cell, known as regulatory T cells, in promoting long-term immunity.
Potential Therapeutic for Blinding Eye Disease
NIH research points to microglia as potential therapeutic target in retinitis pigmentosa.
Potential New Class of Cancer Drugs
Scientists have found a way to stop cancer cell growth by targeting the Warburg Effect, a trait of cancer cell metabolism that scientists have been eager to exploit.
Global Search for Next Antibiotic
University of Queensland researchers have launched a global search to discover antibiotics capable of combating superbug bacteria that are resistant to current antibiotics.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!