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Locating and Explaining ‘Activity Cliffs’ in SAR Datasets


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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.

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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.

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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.
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