Non-peptide peptidomimetic library

Peptidomimetics are organic molecules that mimic the action of peptides. These molecules may structurally resemble peptides but are distinctly different in terms of their side chains or their molecular backbones. Mimicking protein-protein interactions is a very challenging task in medicinal chemistry: to be considered effective, a small-molecule or peptidomimetic must, at the least, interact with the protein in a way that is similar to the native ligand.

As such, the standard usage of physico-chemical parameters is not considered as the prevailing rule when selecting this library. In this case, the only guidance used is:

•    MW < 550, and
•    LogSW > -4 (important for further considerations on compounds solubility).

The prevailing rule in design & selection of non-peptide peptidomimetics library is the search for molecules with structural motifs that are typical for peptidomimetics (available literature search, Integrity and Reaxys data bases). The following resemblance is considered:

•    Molecules with beta- and gamma-turns;
•    Molecules with conformational constrained amino acids;
•    Unnatural amino acids (and their derivatives) which can be considered as bio-isosteric analogs of natural amino acids;
•    Molecules which contain non-typically substituted natural amino acids (e.g.: CF3, CN, etc.);
•    Natural non-proteinogenic amino acids – those were used as a starting point (a core) for further design / selection of analogous derivatives / and chemical development;
•    Privileged structures – those were also used as a starting point (a core) for further design / selection of analogous derivatives / and chemical development;
•    Molecules with dipeptide-like moieties;
•    Molecules with cis-configuration of amide bond;

After assembling the data base of such prototypes, we deploy pharmacophore and sub-structural searches with additional support of 3D-docking (where possible) to hop the molecules that constitute this non-peptide peptidomimetics library. Its latest generation includes 10,000+ molecules assembled around 300+ diverse scaffolds. Other parameters of this library include:

244 < MW < 549 (426 on average)
1 < HBA (H-bond acceptors) < 12 (5 on average)
0 < HBD (H-bond donors) < 5 (1 on average)
0 < RB (rotatable bonds) < 14 (5 on average)
-1.4 < clogP < 5.5. (2.8 on average)

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Discovery
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B = Strong Basic moieties. Constrained Peptidomimetic: Tetrahydroquinones