A component of Forge, Activity Atlas is a new method for summarizing the SAR for a series into a visual 3D model that can be used to inform new molecule design. Activity Atlas is particularly useful for those project teams where there is not enough SAR for a traditional 3D-QSAR approach.
Activity Atlas calculates and displays as 3D visualizations:
- ‘Activity Cliff Summary’: what do the activity cliffs tell us about the SAR?
- ‘Average of actives’: what do active molecules have in common?
- ‘Regions explored’: where have I been? For a new molecule, would making it increase our understanding? This analysis also calculates a novelty score for each molecule.
‘Activity Cliff Summary’
The Activity Cliff Summary maps are derived from the Activity Miner module, summarizing the activity cliff data across the series into a simple map of the critical points in the SAR. In this way, you can build up interpretations of the activity landscape around a compound.
Figure 1 shows the Activity Cliff Summary for Adenosine A1, Adenosine A2a and Adenosine A3 receptor activity data for a data set of compounds published by J. Bajorath (J. Chem. Inf. Model. 51, 258-266, 2011). Critical regions for SAR at the three Adenosine receptors can be easily visualized and used to inform new molecule design aimed, for example, at maintaining potency at the A1 receptors while building in selectivity towards A2 and A3.
Figure 1: Activity Cliff Summary for Adenosine A1 (left); Adenosine A2a (middle); and Adenosine A3 (right).
Color coding of maps: Red: more positive increases activity; Blue: more negative increases activity; Green: steric bulk in this position is favorable; Magenta: steric bulk in this position is detrimental.
‘Average of actives’ analysis
The average of actives analysis gives a similar picture about what the average active molecules look like. The analysis is carried out for electrostatics, hydrophobics and shape. This gives a very helpful overall picture of what new molecules should look like to be active.
‘Regions explored’ analysis
The third and final Activity Atlas model is similar to the Average of Actives analysis, but disregards biological activity completely. Its objective is to make an assessment of what regions of the aligned molecules have been fully explored: it tells you where you have already been with your project.
This analysis can be used in a predictive sense. We can map proposed molecules against it to see whether the new molecules take you into new regions, or only send you to places that you have been before.
- Tackling selectivity with Activity Atlas: In this case study, Activity Atlas was used to analyze the SAR of a series of adenosine A1, adenosine A2a and adenosine A3 antagonists, with the objective to investigate and understand the electrostatic, hydrophobic and shape features underlying receptor selectivity.
- Converting patent data into 3D maps of SAR: This case study uses Activity Atlas to analyze the SAR of a large data set of Orexin-2 receptor ligands taken from the patent literature to rapidly investigate and understand the electrostatic, hydrophobic and shape features of each recently published scaffold.
Web clip: Navigating complex SAR with Activity Atlas
This web clip shows how to navigate complex SAR in Activity Atlas in Forge.