Practical guide to 3D macrocycle modelling
While traditional small molecules excel at targeting buried active sites, they often struggle with shallow, solvent-exposed binding sites. Macrocyclic compounds offer a promising alternative, binding with better affinity and selectivity to address previously “undruggable” targets.
However, macrocycles are much more difficult to model using traditional computational methods due to their size and flexibility. For practical drug discovery, we need modelling that is both accurate and fast enough to integrate into design-make-test cycles.
In this eBook, we explore the three principles that have transformed our ability to accurately predict macrocyclic behaviour, making it possible to routinely use 3D macrocycle modelling in hit-to-candidate workflows.
- Sample the full conformational ensemble, guided by experimental data
- Make strain part of every design decision
- Combine complementary methods, and test them realistically
