Mimicking bioactive conformations of peptide segments involved in the formation of protein-protein interfaces with small molecules is thought to represent a promising strategy for the design of protein-protein interaction (PPI) inhibitors. For compound design, the use of three-dimensional (3D) scaffolds rich in sp3-centers makes it possible to precisely mimic bioactive peptide conformations. Herein, we introduce DeepCubist, a molecular generator for designing peptidomimetics based on 3D scaffolds. Firstly, enumerated 3D scaffolds are superposed on a target peptide conformation to identify a preferred template structure for designing peptidomimetics. Secondly, heteroatoms and unsaturated bonds are introduced into the template via a deep generative model to produce candidate compounds. DeepCubist was applied to design peptidomimetics of exemplary peptide turn, helix, and loop structures in pharmaceutical targets engaging in PPIs.
New matrix metalloproteinase 1 (MMP-1) inhibitors were predicted using the structure–activity relationship (SAR) transfer method based on a series of analogues of kinesin-like protein 11 (KIF11) inhibitors. Compounds 5–7 predicted to be highly potent against MMP-1 were synthesized and tested for MMP-1 inhibitory activity. Among these, compound 6 having a Cl substituent at the R1 site was found to possess ca. 3.5 times higher inhibitory activity against MMP-1 than the previously reported compound 4. The observed potency was consistent with the presence of an SAR transfer event between analogous MMP-1 and KIF11 inhibitors. Pharmacophore fitting revealed that the higher inhibitory activity of compound 6 compared to compound 4 against MMP-1 might be due to a halogen bond interaction between the Cl substituent of compound 6 and residue ARG214 of MMP-1.
Asymmetric construction of densely functionalized three-dimensional aza-tetracyclic scaffolds were achieved by intramolecular Diels–Alder reaction of bicyclic precursors derived from L-tyrosine. Three substituents were systematically introduced into the developed scaffolds in...
A novel sp3 carbon‐rich tricyclic 3D scaffold‐based peptide mimetic compound library was constructed to target protein‐protein interactions. Tricyclic framework 7 was synthesized from 9‐azabicyclo[3,3,1]nonan‐3‐one (11) via a gold(I)‐catalyzed Conia‐ene reaction. The electron‐donating group on the pendant alkyne of cyclization precursor 12 b–e was the key to forming 6‐endo‐dig cyclized product 7 with complete regioselectivity. Using the synthetic strategy for regioselective construction of bridged tricyclic framework 7, a diazatricyclododecene 3D‐scaffold 8 a, which enables the introduction of substituents into the scaffold to mimic amino acid side chains, was designed and synthesized. The peptide mimetics 21 a–u were synthesized via step‐by‐step installation of three substituents on diazatricyclododecene scaffold 8 a. Compounds 21 a–h were synthesized as α‐helix peptide mimics of hydrophobic ZZxxZ and ZxxZZ sequences (Z=Leu or Phe) and subjected to cell‐based assays: antiproliferative activity, HIF‐1 transcriptional activity which is considered to affect cancer malignancy, and antiviral activity against rabies virus. Compound 21 a showed the strongest inhibitory activity of HIF‐1 transcriptional activity (IC50=4.1±0.8 μM), whereas compounds 21 a–g showed antiviral activity with IC50 values of 4.2–12.4 μM, suggesting that the 3D‐scaffold 8 a has potential as a versatile peptide mimic skeleton.
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