Automated Design of Macrocycles for Therapeutic Applications: From Small Molecules to Peptides and Proteins

Macrocycles
and cyclic peptides are increasingly attractive therapeutic
modalities as they often have improved affinity, are able to bind
to extended protein surfaces, and otherwise have favorable properties.
Macrocyclization of a known binder may stabilize its bioactive conformation
and improve its metabolic stability, cell permeability, and in certain
cases oral bioavailability. Herein, we present implementation and
application of an approach that automatically generates, evaluates,
and proposes cyclizations utilizing a library of well-established
chemical reactions and reagents. Using the three-dimensional (3D)
conformation of the linear molecule in complex with a target protein
as the starting point, this approach identifies attachment points,
generates linkers, evaluates their geometric compatibility, and ranks
the resulting molecules with respect to their predicted conformational
stability and interactions with the target protein. As we show here
with prospective and retrospective case studies, this procedure can
be applied for the macrocyclization of small molecules and peptides
and even PROteolysis TArgeting Chimeras (PROTACs) and proteins.