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Protein Mimetics Library

Selected molecules able to mimic common protein motifs

8 960 compounds

Over 250 000 individual protein-protein interactions (PPIs) were identified in human proteome. Although many of these exhibit topologically complex and formidable surface areas, in many instances the successful binding is attained via a limited number of key residues ("hot spots“). There are multiple reports in the literature describing both computational and diversity-oriented approaches to developing small-molecule modulators of PPIs. Of these, non-peptidic a-helix and b-turn imetics are of particular importance due to their key role in multiple deregulated pathways leading to cancer, neurodegenerative disorders, inflammation and immunological disorders.

Most popular library formats

Item
Catalog No.
Compounds
Plates
Amount
Format

Item

1

Catalog No.

PML-9-Y-0

Compounds

8 960

Plates

28

Amount

≤ 300 nL of 2 mM solutions in DMSO

Format

384-well micro plates, Greiner Cat. No. 784201; 320 compounds per plate 1, 2 & 23, 24 columns empty

Item

2

Catalog No.

PML-9-Y-10

Compounds

8 960

Plates

28

Amount

10 µL of 10 mM
DMSO stock solutions

Format

384-well microplates, Echo Qualified,
320 compounds per plate, first two and last two columns empty

Item

3

Catalog No.

PML-9-X-50

Compounds

8 960

Plates

112

Amount

50 µL of 10 mM
DMSO solutions

Format

96-well microplates, 80 compounds per plate, first and last columns empty

Library Design

Target based approach. We carried out design of a focused compound set targeting selected alpha-helix domains and beta-turns such as mdm2-p53, mdm2-CK1α, HIF1-α , MEF2-HDAC4, HIV-1 gp41, CD81/CV, Bcl-2/Bcl-xL, etc. After the selection by virtual screening the preference was set to the structures bearing new chemotypes.

‘Traditional’ three-residue appraoch included design of compounds with unusual cores bearing regular key-residues that mimics i, i+3/i+4 and i+7-residues located on the one recognition face (‘hot spots’). In modeling a-helix interfaces, we accounted also two-face helix mimetics. For beta-turn mimetics we applied three query models with distinct types of interaction: π-π stacking, cation-π and H-bond interaction, S-π interaction. : The latter focused design exercise was exemplified by modeling the interaction between Bim BH3 domain with Mcl-1 and Bcl-2 and identifying fused polyhydrogenated aza-heterocycles with high Fsp3 character.

Ligand based approach. New chemotypes with close topology to known alpha-helix and beta-turns mimetics were selected. Shape based similarity and Pharmacophore screening were used as a main tools for the library design.

Unique Fsp3-enriched scaffolds exhibiting ladder-like cyclic skeletons were specially selected to enhance topological and pharmacophore interaction with the target alpha-helix and beta-turn motifs.

Traditional three residue approach

Alpha-helix Mimetics

Beta-turn Mimetics


Ligand-based approach

Examples of Selected Scaffolds in the Library

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