The last decades witnessed the discovery of a significant number of biologically active peptides, including hormones, vasoactive peptides, and neuropeptides, as described in the literature [1]. Due to their interaction with their membrane-bound receptors, these bioactive peptides influence cell-cell communication, participate in protein-protein interactions (PPI) and cellular signaling, and control other vital functions [2-3]. For this reason, they attracted significant interest in biomedicine, with a growing number of native and modified peptides being used as therapeutics [4].
It is known that peptidomimetics are organic molecules designed to mimic essential elements (pharmacophores) of natural peptides or proteins in 3D space. They retain the ability to interact with biological targets and produce similar biological effects. Peptidomimetics aim to address concerns associated with natural peptides, such as susceptibility to proteolysis and poor bioavailability, while enhancing receptor affinity, selectivity, potency, metabolic stability, and bioavailability. Therefore, the design and synthesis of peptidomimetics are estimated to become remarkably promising in drug discovery [4].
Our cheminformatics team presents a dedicated Peptidomimetic Screening Library of over 7,200 α-helix and β-turn mimetics selected from the proprietary HTS Compound Collection with a ligand-based approach.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
The compound selection can be customized based on your requirements. Cherry-picking is available.
A Pre-plated Peptidomimetic Screening Set based on this Screening Library can be found in our diverse collection of Pre-plated Focused Libraries.
Background information
In spite of the vital importance of natural peptides, their therapeutic potential is limited due to rapid enzymatic degradation in the body. Biomedical research continuously aims to develop novel therapeutics based on peptides and proteins, incorporating structural and functional modifications while preserving biological activity, known as peptidomimetics (Fig. 1). In this strategy, peptides and proteins serve as templates for discovering other compound classes [5-6]. Peptidomimetics are engineered to resist enzymatic degradation, prolonging their half-life and enhancing their efficacy as drugs. Additionally, peptidomimetics offer improved specificity and potency. Scientists can design peptidomimetics that tightly bind to target proteins with high specificity through precise molecular structure adjustments, minimizing off-target and potential side effects. This precise targeting ability makes them attractive for developing treatments for various diseases, from cancer to autoimmune disorders.
![Peptidomimetics. Picture credit: Lenci, E at al., 2020 [1]](img/library_descriptions/Peptidomimetic%20Library/Peptidomimetic_library_1.png "Peptidomimetics. Picture credit: Lenci, E at al., 2020 [1]")
Figure 1. Classification of peptidomimetics
Various synthetic strategies have been developed to manipulate the conformational flexibility and peptide-like characteristics of peptidomimetic compounds. This includes the incorporation of unnatural amino acids (e.g., beta-amino acids, alanine derivatives) and amino alcohol moieties into peptidomimetic scaffolds. Synthetic compounds can mimic peptide secondary structures, such as α-helix, β-turn, and β-strand. Recent advances in peptidomimetic design involve the use of macrocyclic structures, foldamers, and hybrids that combine peptide and non-peptide elements. These advancements enhance stability, cell permeability, and therapeutic efficacy by improving selectivity against non-target receptors [7-11].
Compound selection
This Screening Set was prepared utilizing various similarity analysis techniques, in particular structural similarity search vs. known peptidomimetic inhibitors and scaffolds, 3D shape screening, pharmacophore screening, and complex substructure search:
- 2D similarity analysis was performed against peptidomimetic inhibitors and scaffolds with the Tanimoto index ≥ 0.8 from known databases: PubChem, ChEBI, ChEMBL, and FoldamerDB
- 3D shape screening was performed by Pharmacophore Types volume scoring against more than 1 million conformers generated from the Life Chemicals HTS Compound Collection. It was based on 3D structures of alpha-helices and beta-turns (type I and II), obtained with quantum mechanics calculations
- Pharmacophore screening included pharmacophore model construction based on 3D structures of β-turns (type I and II) obtained through quantum mechanics calculations. The model contained specific exclusion volume constraints and donor/acceptor atom positions to allow hydrogen bond formation in β-turn mimetics (Fig. 2)
- Complex substructure search involved search queries constructed on the basis of α-helix and β-turn peptidomimetic scaffolds from literature, including various bicyclic, spiro, macrocyclic, pyrrolidine, terphenyl, oligo benzamide, anthracene, and other scaffolds (Fig. 3)
- Structure-based virtual screening was performed using Phase (ligand). The reference was a peptidomimetic with inhibitory activity against Human Cytomegalovirus Protease (PDB ID: 1NJT) [12] (Fig. 4)
Figure 2. Compound F1885-0329 aligned against pharmacophore sites. An example of a pharmacophore search based on the β-turn structure.
Figure 3. Some representative scaffolds used for the construction of the search queries.
Figure 4. Pharmacophore model of peptidomimetics with inhibitory activity against Human Cytomegalovirus Protease. The vectors of the model were chosen based on the core of the compound repeating the β-turn.
Chemical space encompasses the vast diversity of chemical entities facilitating the representation of their physicochemical properties, structural features, and potential biological activities. To define key features of the peptidomimetics library obtained, we conducted chemoinformatic analysis by calculating molecular descriptors and conducting chemical space creation and subsequent visualization (Figure 5) [13].
Figure 5. General chemical space hex grid visualization with representative compounds as Murcko scaffolds. Color intensity represents the number of compounds in each hex. It was built using the UMAP dimensionality reduction method.
Representative compounds from the Peptidomimetic Inhibitor Library
References:
- Wang L, Wang N, Zhang W, Cheng X, Yan Z, Shao G, Wang X, Wang R, Fu C. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther. 2022 Feb 14;7(1):48. doi: 10.1038/s41392-022-00904-4. PMID: 35165272; PMCID: PMC8844085.
- Cunningham AD, Qvit N, Mochly-Rosen D. Peptides and peptidomimetics as regulators of protein-protein interactions. Curr Opin Struct Biol. 2017;44:59-66. doi:10.1016/j.sbi.2016.12.009
- Monti, Alessandra, et al. “Targeting Protein-Protein Interfaces with Peptides: The Contribution of Chemical Combinatorial Peptide Library Approaches.” International journal of molecular sciences vol. 24,9 7842. 25 Apr. 2023, doi:10.3390/ijms24097842
- Lenci, E.; Trabocchi, A. Peptidomimetic Toolbox for Drug Discovery. Chem. Soc. Rev. 2020, 49 (11), 3262–3277.
- Corbière A, Vaudry H, Chan P, et al. Strategies for the Identification of Bioactive Neuropeptides in Vertebrates. Front Neurosci. 2019;13:948. doi:10.3389/fnins.2019.00948
- Ji, Xinjian, et al. “Cyclic Peptides for Drug Development.” Angewandte Chemie (International ed. in English) vol. 63,3 (2024): e202308251. doi:10.1002/anie.202308251
- Haque, Muhammed, et al. “Aromatic oligoesters as novel helix mimetic scaffolds.” Bioorganic & medicinal chemistry vol. 87 (2023): 117311. doi:10.1016/j.bmc.2023.117311
- Andrew J. Wilson, Helix mimetics: Recent developments, Progress in Biophysics and Molecular Biology (2015), doi:10.1016/j.pbiomolbio.2015.05.001.
- Dewis, Lydia I et al. “Conformationally Controlled sp3 -Hydrocarbon-Based α-Helix Mimetics.” Angewandte Chemie (International ed. in English) vol. 62,23 (2023): e202301209. doi:10.1002/anie.202301209
- Hirschmann, Ralph F et al. “The beta-D-glucose scaffold as a beta-turn mimetic.” Accounts of chemical research vol. 42,10 (2009): 1511-20. doi:10.1021/ar900020x.
- Laxio Arenas, José, et al. “Peptides and peptidomimetics as inhibitors of protein-protein interactions involving β-sheet secondary structures.” Current opinion in chemical biology vol. 52 (2019): 157-167. doi:10.1016/j.cbpa.2019.07.008
- Khayat R, Batra R, Qian C, Halmos T, Bailey M, Tong L. Structural and biochemical studies of inhibitor binding to human cytomegalovirus protease. Biochemistry. 2003;42(4):885-891. doi:10.1021/bi027045s
- Sorkun MC, Mullaj D, Vianney JM, Koelman A, Er S. ChemPlot, a Python Library for Chemical Space Visualization. Chemistry—Methods. 2022; vol. 2, iss. 7. doi: 10.1002/cmtd.202200005