Free Energy Perturbation (FEP): Another technique in the drug discovery toolbox
Introduction When I first started using CHARMM over 20 years ago as a PhD student, I regularly came across references ...
During the 246th ACS National Meeting and Exhibition Fall 2013, we presented during the COMP session on ‘Finding and using activity cliffs in 3D: Gaining more SAR information during lead optimization’. The abstract and presentation are below.
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 extracting this information from the data set to determine the optimal compound to synthesize next is a challenging task.
One technique to extract the most important chemical transformations in a data set is to locate pairs of compounds where relatively small structural changes cause relatively large potency changes. This technique was used at Merck in the 1990s where it was called ‘disparity analysis’, but has recently become widely known as ‘activity cliffs’. 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 analysis.
The assessment of activity cliffs has largely been done in 2D. However, the interpretation of 2D activity cliffs can be difficult. A small structural change could cause a large change in potency because of steric clash with the protein, the loss of (or gain of) pharmacophoric features such as hydrogen bond donors/acceptors, or through forcing a different conformational profile on the ligand. In this talk we present a technique for locating activity cliffs in molecular field space, where pairs of molecules are emphasized if their electrostatics and shape are similar but their potency is very different. Such pairs give detailed insight into the important 3D properties required for potency. We also show that combining 2D and 3D activity cliff analysis can lead to an improved understanding of the source of the large change in potency, and hence help the chemist to truly understand the SAR of their compounds.