Conformational Strain of Macrocyclic Peptides in Ligand-Receptor Complexes Based on Advanced Refinement of Bound-State Conformers.

Alexander C. Brueckner,Edward C. Sherer,Ajay N. Jain,Ann E. Cleves,Charles A. Lesburg,Juan C. Alvarez,Qiaolin Deng,Mikhail Y. Reibarkh

doi:10.1021/acs.jmedchem.0c02159

Alexander C. Brueckner, Edward C. Sherer + Show 6 more

Open Access

https://doi.org/10.1021/acs.jmedchem.0c02159

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Abstract

Macrocyclic peptides are an important modality in drug discovery, but molecular design is limited due to the complexity of their conformational landscape. To better understand conformational propensities, global strain energies were estimated for 156 protein-macrocyclic peptide cocrystal structures. Unexpectedly large strain energies were observed when the bound-state conformations were modeled with positional restraints. Instead, low-energy conformer ensembles were generated using xGen that fit experimental X-ray electron density maps and gave reasonable strain energy estimates. The ensembles featured significant conformational adjustments while still fitting the electron density as well or better than the original coordinates. Strain estimates suggest the interaction energy in protein-ligand complexes can offset a greater amount of strain for macrocyclic peptides than for small molecules and non-peptidic macrocycles. Across all molecular classes, the approximate upper bound on global strain energies had the same relationship with molecular size, and bound-state ensembles from xGen yielded favorable binding energy estimates.

Highlights

Protein−protein associations are often mediated through large and relatively flat surfaces (1500−3000 Å2), to which drug-like small molecules (
Macrocyclic peptides represent a therapeutic modality that has the potential to combine the best properties of small molecule ligands and antibodies.[4,9,16−22] Macrocyclization of peptides constrains conformational space and imparts some structural preorganization, thereby decreasing the number of low-energy conformations.[4,7,16,23−31] This reduces the entropic penalty of binding and increases proteolytic stability compared to acyclic peptides.[32−34]
The majority of the structures were deposited between 2010 and 2017, highlighting the increased interest in macrocyclic peptides as therapeutics in recent years (Figure 1B).[4,40−44] Peptide sizes ranged from 4 to 24 residues with the bulk of the data set between 5 and 14 residues (Figure 1C). This size range bridges the gap between small molecules (