Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria

Abstract

N-anilinoethylamides are a class of melatoninergic agents with the aniline portion mimicking the indole ring of the natural ligand and the ethylamide chain reproducing that of melatonin. The simplest compound in this class, N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (UCM793), has nanomolar binding affinity for MT1 and MT2 membrane receptors. To explore the effect of chain conformation on receptor binding, a methyl group was inserted on the methylene alpha or beta to the amide nitrogen and conformational equilibria were investigated by NMR spectroscopy and molecular dynamics simulations. Receptor affinity was conserved only for the beta-methyl derivative, which also showed significant stereoselectivity, with the (S) enantiomer being the eutomer. Molecular dynamics simulations, validated by NMR spectroscopy, showed that the beta-methyl group affects the conformational preferences of the ethylamide chain. Docking into the receptor crystal structure provides a rationale for the observed chiral recognition, suggesting that the (S)-beta-methyl group favors the conformation that better fits the receptor binding site.

Facile synthesis of new N-(aminocycloalkylene)amino acid compounds using chiral triflate esters with N-Boc-aminopyrrolidines and N-Boc-aminopiperidines

“…The synthetic sequence was started by transforming a-hydroxy carboxylates (R)-1a and (S)-1a into the triate esters, methyl(2R)-and (2S)-2-[(tri-uoromethanesulfonyl)oxy]propanoates (R)-2a and (S)-2a, using triuoromethanesulfonic anhydride and pyridine in DCM. 28 A triate group is an excellent leaving group used in nucleophilic substitution reactions and has been shown to be signicantly superior to other leaving groups in the Walden inversion, where the inversion of a stereogenic centre in a chiral molecule takes place. 29,30 It is known that the reaction of enantiopure a-halocarboxylic acid esters with amines is accompanied by extensive racemization of a-amino esters; with a-methanesulfonyloxy and a-toluenesulfonyloxy carboxylic acid derivatives, both racemization and elimination products are formed due to the drastic conditions.…”

Molecular Determinants of EphA2 and EphB2 Antagonism Enable the Design of Ligands with Improved Selectivity

“…Two variables, χ1 and χ2, were selected to monitor the rotation of the rotatable bonds describing the position of the indole ring within the LBD of both EphA2 and EphB2 receptors. Similar approaches have been applied to explore the conformational space of biologically active ligands in the condensed phase to rationalize protein–ligand binding or to obtain key insights for drug design. , …”

“…Similar approaches have been applied to explore the conformational space of biologically active ligands in the condensed phase to rationalize protein−ligand binding 46 or to obtain key insights for drug design. 47,48 Analysis of a 2.5 μs MD simulation of EphA2 in complex with UniPR1447 showed that the ligand experienced transitions between alternative configurations, as indicated by the temporal evolution of χ1 and χ2 dihedral angles (Figure S3, SI). The global minimum corresponded to the best-ranked configuration found by docking (pose 1), with χ1 and χ2 values close to −60 and 0°, respectively.…”

Chiral separation and molecular simulation study of six antihistamine agents on a coated cellulose tri‐(3,5‐dimethylphenycarbamate) column (Chiralcel OD‐RH) and its recognition mechanisms

“…To our knowledge, molecular docking could provide the information of stereo‐dependent binding sites and binding energy between the chiral analytes and CSP, and could gain a better understanding of the chiral recognition mechanisms [49,50]. The previous literature for CDMPC and related polymers revealed that the side chains surrounding the helical polymer backbones could create nano‐sized chiral cavities [36].…”