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

Abstract

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 andcyclic peptides as attractive therapeutic modalities. File list (2) download file view on ChemRxiv DesignOfMacrocycles_chemrxiv.pdf (1.85 MiB) download file view on ChemRxiv SUPPORTING INFORMATION.pdf (458.87 KiB)

Potentials of Neuropeptides as Therapeutic Agents for Neurological Diseases

“…This could lead to both increased target affinity and reduced drug development time [ 272 ]. The recent development of computer algorithms that can generate and screen novel macrocyclic molecules from small peptides could lead to significant advancements in the effectiveness of peptide therapeutics by enhancing understanding of how the structure of macrocyclic peptides relates to their activity [ 273 ].…”

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

“… 123 In the second case, macrocyclization is a design strategy for locking a known binder into its bioactive conformation and improving its PD profile. 124 Already 19 macrocyclic drugs, including three radiopharmaceuticals, have been approved by the FDA for the treatment of infectious and metabolic diseases, cancer, immunosuppression, etc. 125 …”

“…In this respect, to facilitate macrocyclization of PROTACs, a computational method has been proposed to automatically generate feasible cyclization by known chemical reactions. 124 Moreover, this approach identifies attachment points, evaluates geometric compatibility, and ranks the resulting macrocyclic molecules by their predicted conformational stability with the target protein. 124 …”

“… 124 Moreover, this approach identifies attachment points, evaluates geometric compatibility, and ranks the resulting macrocyclic molecules by their predicted conformational stability with the target protein. 124 …”

Genetically-encoded discovery of proteolytically stable bicyclic inhibitors for morphogen NODAL

“…10 Introduction of a bridgehead into macrocyclic topologies to form so-called bicyclic peptides could further decrease conformational exibility and increase stability or binding potency. 5,11 Bioactive bicyclic peptides that have been reported thus far originate from natural products, 12 computational approaches, [13][14][15] cyclization of known bioactive peptides, [16][17][18][19] or screening of combinatorial libraries. [20][21][22] To fuel the last method, synthesis on the solid support can yield libraries of 10 2 -10 5 diversity, [20][21][22] whereas latestage chemical diversication of biosynthesized peptides displayed on mRNA 11,[23][24][25] or phage 26,27 can give rise to bicyclic libraries with 10 9 -10 12 diversity.…”