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

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

Fragment-Based Screening Maps Inhibitor Interactions in the ATP-Binding Site of Checkpoint Kinase 2

Checkpoint kinase 2 (CHK2) is an important serine/threonine kinase in the cellular response to DNA damage. A fragment-based screening campaign using a combination of a high-concentration AlphaScreen™ kinase assay and a biophysical thermal shift assay, followed by X-ray crystallography, identified a number of chemically different ligand-efficient CHK2 hinge-binding scaffolds that have not been exploited in known CHK2 inhibitors. In addition, it showed that the use of these orthogonal techniques allowed efficient discrimination between genuine hit matter and false positives from each individual assay technology. Furthermore, the CHK2 crystal structures with a quinoxaline-based fragment and its follow-up compound highlight a hydrophobic area above the hinge region not previously explored in rational CHK2 inhibitor design, but which might be exploited to enhance both potency and selectivity of CHK2 inhibitors