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 interfaces and otherwise have favorable
properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive
conformation, improve its metabolic stability, cell permeability and in certain cases oral
bioavailability. Herein, we present an in silico 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
starting point, this approach identifies attachment points, generates linkers, evaluates the
conformational landscape of suitable linkers and 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 several prospective and retrospective case studies, this procedure can
be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.
The presented approach is an important step towards the enhanced utilization of macrocycles and
cyclic peptides as attractive therapeutic modalities.