Increasing Selectivity of CC Chemokine Receptor 8 Antagonists by Engineering Nondesolvation Related Interactions with the Intended and Off-Target Binding Sites
posted on 2009-12-10, 00:00authored byIgor Shamovsky, Chris de Graaf, Lisa Alderin, Malena Bengtsson, Håkan Bladh, Lena Börjesson, Stephen Connolly, Hazel J. Dyke, Marco van den Heuvel, Henrik Johansson, Bo-Göran Josefsson, Anna Kristoffersson, Tero Linnanen, Annea Lisius, Roope Männikkö, Bo Nordén, Steve Price, Lena Ripa, Didier Rognan, Alexander Rosendahl, Marco Skrinjar, Klaus Urbahns
The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERG ion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656.