Matijssen, C. and Kinsella, G.K. and Watson, G.W. and Rozas, I.
(2012)
Computational study of the proton affinity
and basicity of structurally diverse
a1-adrenoceptor ligands.
Journal of Physical Organic Chemistry, 25.
pp. 351-360.
ISSN 0894-3230
Abstract
The a1-adrenoceptor is a target for the treatment of several conditions from hypertension to benign prostatic
hyperplasia. In this paper, we describe a new analysis approach to explore the conformational space of several
ligands of the a1-adrenoceptor and we also present the calculation of their proton affinity and basicity. For each
compound a conformational search followed by a semi-empirical optimisation was performed and a selection of
conformations for each ligand was subjected to further optimisation using density functional theory methods.
Different positions were explored to determine the favoured site of protonation, and then, the proton affinity (in the
gas phase) and basicity (using the polarisable continuum model for the aqueous solution) were calculated for each of
them. In addition, an alternative method using one explicit water molecule in combination with the polarisable
continuum model for aqueous solvent was explored. Moreover, the acid dissociation constant (pKa) in water of these
26 compounds was calculated because this is an important parameter for a ligand when binding to its receptor. The
experimental pKa values of six of these ligands and those of two compounds with a very low and a very large pKa were
used to validate the theoretical methodology.
| Item Type: |
Article
|
| Additional Information: |
This work was funded by a postgraduate studentship from the
University of Dublin and by the HEA under the IITAC-PRTLI (Cycle
III) grant. All calculations were performed on the IITAC cluster
maintained by the Trinity Centre for High Performance Computing
(Ireland) and on the CTI belonging to the CSIC (Spain). |
| Keywords: |
acid dissociation constant; a1-adrenoceptor; basicity; polarisable continuum model; proton affinity; |
| Academic Unit: |
Faculty of Science and Engineering > Biology |
| Item ID: |
5421 |
| Identification Number: |
https://doi.org/10.1002/poc.1940 |
| Depositing User: |
Gemma Kinsella
|
| Date Deposited: |
24 Sep 2014 15:31 |
| Journal or Publication Title: |
Journal of Physical Organic Chemistry |
| Publisher: |
Wiley |
| Refereed: |
Yes |
| URI: |
|
| Use Licence: |
This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available
here |
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