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Alpha-helix Mimetics

9 900 compounds

It is estimated that there are over 250 000 individual protein-protein interactions (PPIs) in human proteome. Although many of them 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 α-helix mimetics are of particular importance due to their key role in multiple deregulated pathways leading to cancer, neurodegenerative disorders, inflammation and immunological disorders.

Library design included:

Target based approach (Fig. 1a)

We carried out design of focused set towards selected alpha-helix domains as mdm2-p53, mdm2-CK1α, HIF1-α, MEF2-HDAC4, HIV-1 gp41, CD81/CV, Bcl-2/Bcl-xL, etc. During the selection by virtual screening the preference was given to novel chemotypes.

‘Traditional’ three-residue approach (Fig. 1b)

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. 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.

a)Results of virtual screening on mdm2-p53 b)Design of potent α-helix mimetics using three-residue approach

Figure 1. Results of virtual screening on mdm2-p53 (a); design of potent α-helix mimetics using three-residue approach (b)

Ligand based approach (Fig. 2)

New chemotypes with close topology to known alpha-helix mimetics (e.g. Nultins, MI-219, ABT-737, etc.) were selected. On the other hand we designed unique Fsp3-enriched scaffolds exhibiting ladder-like cyclic skeletons that allow for the enhanced topological and pharmacophore interaction with the target alpha-helix.

a) b)

Figure 2. Generation of potent α-helix mimetics by ligand-based approach (a); representative novel scaffolds (b)

Molecular profile (Fig. 3)

Selection of compounds was carried out using strict modern MedChem filters. Most of Library compounds have favorable molecular properties for further development (Ro5 86.2%, leadlikeness 82.7%). During the selection the emphasis is done on compounds with Fsp3-rich chemotypes (average Fsp3 0.46) with diverse 3D-shapes.

Mol Weight LogP

Figure 3. Molecular properties of α-helix mimetics.

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