Can you keep all the SAR in your head?

The poster ‘Can you keep all the SAR in your head? Using biological contexts to find critical SAR regions’ was presented at the 247th ACS National Meeting and Exposition in Dallas on 16th and March 17th.

Abstract

Typically during the lead optimization phase of a drug discovery project, many compounds are synthesized. For each of these compounds you will normally generate a wealth of potency, selectivity and ADMET information. Navigating this complex web of information is a daily challenge for the project team: identifying areas of critical activity – understanding what synthetic decisions to make and guiding the project forwards to the ideal lead candidate.

Locating Activity Cliffs can aid in this analysis, by locating and isolating key areas of SAR, and enabling the project team to focus efforts in the most productive way possible. Activity Cliffs are defined by pairs of compounds where relatively small structural changes result in a large change in activity.

Activity Cliff interpretation can be challenging: a small structural change can result in a large change in potency due to different reasons: steric clash with protein, loss/gain of H bond donors/acceptors, forcing alternate conformation of the ligand etc.

This work presents a technique for locating Activity Cliffs in the context of the target active site. Using this method critical SAR regions are clearly and rapidly identified. Furthermore the reason for the activity differences between pairs of compounds is readily discernible, leading to a true understanding of the SAR landscape.

View the poster here.

You may also be interested our webinar on March 25th ‘Deciphering SAR around aromatics’. Register free here.