Poster presentation at EFMC-ISMC: Can you keep all the SAR in your head? Using biological contexts to find the critical SAR regions


During the course of a lead optimization program hundreds or even thousands of compounds may be synthesized. These compounds hold a wealth of information on potency, selectivity and ADMET properties, but keeping all of this in mind, understanding it and using it to determine the optimal compound to make next is a challenging task. One technique to extract the most important chemical transformations in a data set is to locate ‘activity cliffs’: pairs of compounds where relatively small structural changes cause relatively large potency changes. The idea is that if a small structural change causes a large change in activity, then that structural change has high information content. A similar philosophy underlies the technique of matched molecular pair (MMP) analysis. However, the interpretation of activity cliffs can be difficult. A small structural change could cause a large change in potency due to many different reasons, such as steric clash with the protein, the loss of (or gain of) hydrogen bond donors/acceptors, or through forcing an alternative conformation of the ligand. We present a technique for locating activity cliffs in the context of the target active site. This clearly identifies the most important parts of the SAR, and visually shows the reason for the activity difference between each pair of compounds, assisting in a true understanding of the SAR landscape.

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