Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria

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.

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Molecular interactions between fenoterol stereoisomers and derivatives and the β2-adrenergic receptor binding site studied by docking and molecular dynamics simulations

Journal of Molecular Modeling ◽

10.1007/s00894-013-1981-y ◽

2013 ◽

Vol 19 (11) ◽

pp. 4919-4930 ◽

Cited By ~ 21

Author(s):

Anita Plazinska ◽

Michal Kolinski ◽

Irving W. Wainer ◽

Krzysztof Jozwiak

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Binding Site ◽

Receptor Binding ◽

Molecular Interactions ◽

Adrenergic Receptor ◽

Receptor Binding Site ◽

Β2 Adrenergic Receptor ◽

Dynamics Simulations

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UNDERSTANDING DIFFERENT LCST LEVELS OF POLY(N-ALKYLACRYLAMIDE)S BY MOLECULAR DYNAMICS SIMULATIONS AND QUANTUM MECHANICS CALCULATIONS

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633611006505 ◽

2011 ◽

Vol 10 (03) ◽

pp. 359-370 ◽

Cited By ~ 7

Author(s):

JUAN PANG ◽

HU YANG ◽

JING MA ◽

RONGSHI CHENG

Keyword(s):

Molecular Dynamics ◽

Quantum Mechanics ◽

Aqueous Solutions ◽

Molecular Dynamics Simulations ◽

Steric Effect ◽

Conformational Transition ◽

Methyl Group ◽

Branched Chain ◽

Dynamics Simulations ◽

Different Levels

Poly(N-alkylacrylamide) is a group of thermo-sensitive polymers that include poly (N-isopropylacrylamide), poly(N-n-propylacrylamide), poly(N-isopropylmethacryl-amide), and so on. The polymers exhibit different levels of lower critical solution temperatures (LCST) in aqueous solutions. In this article, their monomers and oligomers with 10 repeating units are selected, respectively, to demonstrate the cause of different LCST levels of the polymers in aqueous solutions using molecular dynamics simulations and quantum mechanics calculations. The monomers have functional groups of different steric volume that greatly affect the conformational transition of chains and LCST levels of the polymers. A branched chain of N-propyl group in N-isopropylacrylamide and an additional methyl group at α-carbon in N-isopropylmethacrylamide both increase the steric effect, making it more difficult for monomers to draw closer and resulting in higher LCST levels of the polymers. In addition, the simulated results from their corresponding oligomers exhibit the similar trend to those from the monomers.

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