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.

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