Comparing protein electrostatics to ligand SAR: Double the fun?

We have recently presented a method (Activity Atlas) of summarizing the information obtained from 3D activity cliff analysis. Examination of all pairs of molecules can distinguish between apparent cliffs that are outliers, or due to measurement error, and those which consistently point to particular electrostatic and steric features having a large impact on activity. As part of this technique, a probabilistic map of the SAR of the series is developed, corrected for the conformational and alignment flexibility of each molecule. This provides an invaluable picture to the chemist showing which parts of property space around a molecule have a strong effect on the activity.

We show a comparison of the activity maps generated with this technique to the electrostatic potential inside the protein active site. Visualizing the active site potential is a powerful way of going beyond simple pharmacophore analysis to reveal the more subtle requirements for strong protein binding. By performing both techniques on several literature data sets we show their complementarity and the usefulness of combining structure-based and ligand-based methods.

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