Automated Design of Macrocycles for Therapeutic Applications: from Small Molecules to Peptides and Proteins
<div>Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have </div><div>improved affinity, are able to bind to extended protein interfaces and otherwise have favorable </div><div>properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive </div><div>conformation, improve its metabolic stability, cell permeability and in certain cases oral </div><div>bioavailability. Herein, we present an in silico approach that automatically generates, evaluates and </div><div>proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the </div><div>three-dimensional (3D) conformation of the linear molecule in complex with a target protein as </div><div>starting point, this approach identifies attachment points, generates linkers, evaluates the </div><div>conformational landscape of suitable linkers and their geometric compatibility and ranks the resulting </div><div>molecules with respect to their predicted conformational stability and interactions with the target </div><div>protein. As we show here with several prospective and retrospective case studies, this procedure can </div><div>be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.</div><div>The presented approach is an important step towards the enhanced utilization of macrocycles and</div><div>cyclic peptides as attractive therapeutic modalities.</div>