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    Computational study of the proton affinity and basicity of structurally diverse a1-adrenoceptor ligands

    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

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    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:
    Depositing User: Gemma Kinsella
    Date Deposited: 24 Sep 2014 15:31
    Journal or Publication Title: Journal of Physical Organic Chemistry
    Publisher: Wiley
    Refereed: Yes
    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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