Peptidomimetic Compound Library

Peptidomimetics are organic molecules that mimic the action of peptides. These molecules are structurally similar to peptides, but differ significantly in terms of their side chains or their molecular backbones. Nowadays, a large number of bioactive peptides have been identified and characterized, including hormones, vasoactive peptides and neuropeptides. Due to interaction with their membrane-bound receptors, these bioactive peptides are able to influence cell-cell communication, participate in protein-protein interactions (PPI), cell signaling and control a range of important functions. Peptidomimetics are compounds whose pharmacophores mimic natural peptides or proteins in 3D space, and are able to retain the ability to interact with biological targets and produce the same biological effects. Peptidomimetics are designed to circumvent some of the problems associated with a natural peptide such as stability to protein hydrolysis, poorer bioavailability. The design and synthesis of peptidomimetics is of utmost importance because peptide and protein-protein interactions play a dominant role in molecular recognition and signaling, especially in living systems. Therefore, mimics have great potential in drug discovery.

To meet the growing demand for new structures for drug discovery projects, BOC Sciences has designed its dedicated peptidomimetic compound library for the application in high-throughput screening (HTS) and high-content screening (HCS) programs.

Figure 1. Comparison of the docked designed peptidomimetic with the EcDsbA-EcDsbB and PmDsbA-PWATCDS crystal structures. (Wilko, D.; et al. 2015)

Library Design

BOC Sciences has developed different synthetic strategies to modulate the conformational flexibility and peptide properties of peptidomimetic compounds. Unnatural amino acids (e.g., β-amino acids, alanine derivatives, etc.) and amino alcohol moieties can be introduced into peptidomimetic scaffolds. Synthetic compounds can be used as peptide secondary structure mimics (α-helix, β-turn and β-chain).

α-Helical Peptidomimetic Library

We have developed two models for each training set. The first one is established based on FCFP6 fingerprint and the second one is based on ECFP6. A variety of molecular descriptors such as LogP, molecular weight, number of hydrogen donors and acceptors, number of rotatable bonds, number of rings and molecular polar surface area are involved in the construction of the models to improve the accuracy

β-Turn Peptidomimetic Library

The library is prepared by applying two selection procedures and diversity clustering. The first selection is performed using pharmacophore screening where the pharmacophore models are based on real β-turn structures, and the second selection is carried out by using similarity search with known scaffolds of β-turn peptidases, such as pentameric and hexameric cyclic scaffolds, bicyclic scaffolds

2D similarity analysis is performed against known peptidomimetic inhibitors and scaffolds
3D shape screening of more than 1 million conformations generated from BOC Sciences HTS compounds collection using pharmacophore type volumes. The model contained specific exclusion volume constraints and donor/acceptor atom positions to allow hydrogen bond formation in β-turn mimics
Complex substructure search involves search queries for α-helix and β-turn peptidomimetic scaffold construction, such as various bicyclic, spiro, macrocyclic, pyrrolidine, triplet, oligobenzamide, anthracene and other scaffolds