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Multi-targeting protein-protein interaction inhibitors: Evolution of macrocyclic ligands with embedded carbohydrates (MECs) to improve selectivity
- Source :
- European Journal of Medicinal Chemistry. 176:292-309
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Compounds targeting multiple proteins can have synergistic effects and are therefore of interest in medicinal chemistry. At the same time, inhibiting protein-protein interactions (PPI) is increasingly desired in the treatment of disorders or diseases. The development of non-peptidomimetic inhibitors is still a challenge. Herein we investigate macrocyclic scaffolds with one or two embedded carbohydrates (MECs) that present amino acid side chains, or related isosteres, as pharmacophoric groups. Firstly, retroscreening of the previously reported eannaphane-40 (E40, 40), a MEC presenting two pharmacophoric groups, against a set of 55 receptor-subtypes led to a finding of sub-micromolar inhibitory activity for E40 against three serotonergic isoforms (5HT1A/2A/2B) as well as the Na+ channel and the NK-2 receptor. We synthesised MECs with an additional pharmacophoric group compared to E40, with a view to identifying compounds where the selectivity profile was altered among the protein hits from the retroscreening. MECs were produced based on scaffolds with two monosaccharide residues, leading to the incorporation of a third pharmacophoric group. Later, homology models were prepared for four proteins (5HT1A, 5HT2A, NK2 and site-2 of the sodium channel) whose 3D structure is unknown. Inverse docking of the synthesised compounds led to the selection of a new MEC (MEC-B) for protein binding assays. MEC-B was found to have its selectivity profile modulated, in line with docking prediction, compared to E40. MEC-B is dual inhibitor of both 5-HT1A and the sodium channel with improved selectivity for these proteins compared to 5-HT2A/2B/2C, 5-HT transporter and NK2 receptor. Thus, a new multitargeting compound, with an improved selectivity profile was identified, based on a MEC peptidomimetic scaffold.
- Subjects :
- Macrocyclic Compounds
Peptidomimetic
Stereochemistry
Plasma protein binding
Ligands
01 natural sciences
Sodium Channels
Protein–protein interaction
03 medical and health sciences
Glucosides
Drug Discovery
Escherichia coli
Animals
Humans
Amino Acid Sequence
Receptor
030304 developmental biology
Serotonin Plasma Membrane Transport Proteins
Pharmacology
chemistry.chemical_classification
0303 health sciences
Binding Sites
010405 organic chemistry
Chemistry
Sodium channel
Organic Chemistry
Proteins
Receptors, Neurokinin-2
General Medicine
0104 chemical sciences
Amino acid
Molecular Docking Simulation
Docking (molecular)
Drug Design
Receptors, Serotonin
Peptidomimetics
Protein Multimerization
Selectivity
Protein Binding
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 176
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....ddced44919b8c1ef6cafc7e394b7b5a2