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Computational study of the proton affinity and basicity of structurally diverse α 1 ‐adrenoceptor ligands
Author(s) -
Matijssen C.,
Kinsella G. K.,
Watson G. W.,
Rozas I.
Publication year - 2012
Publication title -
journal of physical organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.325
H-Index - 66
eISSN - 1099-1395
pISSN - 0894-3230
DOI - 10.1002/poc.1940
Subject(s) - chemistry , protonation , proton affinity , aqueous solution , dissociation constant , ligand (biochemistry) , molecule , computational chemistry , dissociation (chemistry) , substituent , acid dissociation constant , proton , solvent , density functional theory , a value , stereochemistry , receptor , ion , organic chemistry , biochemistry , physics , quantum mechanics
The α 1 ‐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 α 1 ‐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 (p K a ) in water of these 26 compounds was calculated because this is an important parameter for a ligand when binding to its receptor. The experimental p K a values of six of these ligands and those of two compounds with a very low and a very large p K a were used to validate the theoretical methodology. Copyright © 2011 John Wiley & Sons, Ltd.