Molecules containing large rings, or macrocycles, have become of greater and greater interest to the drug discovery community over the past decade. A key part of productively exploiting this class of molecules as therapeutics is understanding their conformational landscape, and there have been a number of different approaches to this problem presented recently.<sup> </sup>Here we will present a new approach to macrocycle conformation sampling based on distance geometry. In the most extensive comparison performed to date in this area we evaluate our method against a wide variety of other algorithms in reproducing conformations found in the solid-state, the most popular approach to validating conformer generators.<br/>While conformations found in the solid-state are easy to validate against, and are relevant to a number of problems in macrocycle design, including pose prediction by docking and structure-guided lead optimization, generating conformations relevant to the solution state is also important. We will present preliminary data on the use of distance geometry to generate conformations in a variety of environments that are consistent with experimental data from NMR spectroscopy and new methods to analyse and interpret these conformational ensembles.

Conformational analysis and visualisation of macrocycles in solution and the solid-state

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.