α-Helix Mimetics Library

Nowadays, scientists have developed a variety of computational and diversity-oriented approaches for the discovery of PPI small molecule modulators. Among them, non-peptide α-helix imetics are particularly important because they play a key role in multiple deregulated pathways leading to cancer, neurodegenerative diseases, inflammation and immune disorders. The α-helix is the most common protein secondary structure, accounting for more than 40% of peptide structures in proteins. Rationally designed compounds are shown to effectively inhibit protein-protein interactions characterized by α helix-mediated binding and recognition.

BOC Sciences has designed an α-helix mimetics library targeting protein-protein interactions that contains members capable of regulating any protein-protein interaction mediated by the α-helix, and will provide a unique resource for interrogating these targets.

Figure 1. Hamilton's α-helix mimetic scaffolds. (Shaginian, A.; et al. 2009)

Library Design

BOC Sciences supports the following three approaches to design our library:

Target-based approach

• We design a focused compound set targeting selected α-helix domains such as mdm2-p53, mdm2-CK1α, HIF1-α, etc. After the selection by virtual screening, preferences are set to structures with new chemical types

‘Traditional’ three-residue approach

• Our groups have designed compounds with unusual cores with regular crucial residues that mimic i, i+3/i+4 and i+7 located on a recognition surface which is also called hot spot
• In addition, we consider two-face helix mimetics when modeling α-helix interfaces

Ligand-based approach

• A series of novel chemotypes with close topology to known α-helix mimetics are selected. Shape-based similarity and pharmacophore screening are applied as main tools for the library design
• Unique Fsp³-enriched scaffolds with a ladder-like cyclic skeleton are specifically selected to enhance topological and pharmacophore interactions with the target α-helix motifs

Figure 2. An overlay of an α-helix mimetic compound with the p53 peptide. (Shaginian, A.; et al. 2009)

α-Helix Mimetics Library Characteristics

• Mimicry of helix by the structure of polycyclic small molecule scaffolds
• Mimicry of side-chain residues on one face of the α-helix
• At least three points of interaction with 7-ala helix
• Possible H-bond, hydrophobic, electrostatic
• Include hydrophilic regions in the scaffolds
• Avoidance of polycyclic aromatics (such as terphenyls and their hetero-analogs, oligobenzamides and their hetero-analogs)
• High Fsp³ for core scaffolds
• High solubility of mimetics
• No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
• Bioactivity and safety confirmed by preclinical studies and clinical trials
• Structural diversity, medicinal activity, and cellular penetration
• Structural document, IC₅₀, and other chemical and biological data are provided
• All compounds are continually updated
• All of these compounds with Tanimoto index ≥ 0.85
• Compound cherry-picking service is provided

What We Deliver

• Delivered within 2 weeks in any customer-preferred format
• Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
• All compounds have a minimum purity of 90% assessed by ¹H NMR and HPLC
• Analytical data is provided

BOC Sciences provides professional, rapid and high-quality services of α-Helix Mimetics Library design at competitive prices for global customers. Personalized and customized services of α-Helix Mimetics Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!