Skip to main content
Article
Computational study of the proton affinity and basicity of structurally diverse α1-adrenoceptor ligands
Journal of Physical Organic Chemistry (2011)
  • Gemma K Kinsella, Dr, Trinity College Dublin
  • C Matijssen, Dr, Trinity College Dublin
  • Graeme W Watson, Prof, Trinity College Dublin
  • Isabel Rozas, Prof, Trinity College Dublin
Abstract

The α1-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 α1-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.

Keywords
  • acid dissociation constant,
  • α1-adrenoceptor,
  • basicity,
  • polarisable continuum model,
  • proton affinity
Publication Date
Winter October 25, 2011
Citation Information
Gemma K Kinsella, C Matijssen, Graeme W Watson and Isabel Rozas. "Computational study of the proton affinity and basicity of structurally diverse α1-adrenoceptor ligands" Journal of Physical Organic Chemistry Vol. 25 Iss. 4 (2011)
Available at: http://works.bepress.com/gemma_kinsella/6/