Jump to main content
Jump to site search

Issue 39, 2015
Previous Article Next Article

The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study

Author affiliations

Abstract

N-Methylation has a significant impact on improving the oral bioavailability, lipophilicity and aqueous solubility of peptide-based lead drug structures. The selected mono-amino acid derivatives Ac-X-OMe, where X = Gly, Val, Leu, Ile, Phe, Met, Cys, Ser, Asp and His as well as their corresponding N-methylated analogues were studied. The clog P values of all N-methylated peptides are greater than those of native compounds. Quantum chemical calculations were performed to estimate the aqueous solubility of these lipophilic compounds using density functional theory (DFT). To confirm the contribution of dispersion forces on quantum chemical data, the long-range corrected (LC) hybrid density functional (ωB97X-D) was also probed for some amino acid derivatives. The ωB97X functional gave similar results. Our results reveal that after mono N-methylation of the peptide backbone, ΔGsolv becomes more negative (more water soluble) while polarizability and dipole moment are also increased. Natural atomic charges derived by natural bond orbital (NBO) analysis of N, C, and O atoms involved in amide functional group become more positive/(less negative) after N-methylation. All N-methylated amino acids have higher EHOMO (less negative) in comparison with the amino acid analogues, and in all cases N-methylation decreases EHOMO–LUMO. The calculated amide cis/trans activation energies (EA) of all the N-methylated amino acid derivatives were lower than that of native species. N-methylation of these compounds leads to an increase in lipophilicity, aqueous solubility, polarization, dipole moment and lowering of the cis/trans amide energy barrier (EA).

Graphical abstract: The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study

Back to tab navigation

Supplementary files

Article information


Submitted
28 Jul 2015
Accepted
11 Aug 2015
First published
11 Aug 2015

Org. Biomol. Chem., 2015,13, 9993-10006
Article type
Paper
Author version available

The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study

S. Md. Abdur Rauf, P. I. Arvidsson, F. Albericio, T. Govender, G. E. M. Maguire, H. G. Kruger and B. Honarparvar, Org. Biomol. Chem., 2015, 13, 9993 DOI: 10.1039/C5OB01565K

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.


Social activity

Search articles by author

Spotlight

Advertisements