Shamovsky, Igor Graaf, Chris de Alderin, Lisa Bengtsson, Malena Bladh, Håkan Börjesson, Lena Connolly, Stephen Dyke, Hazel J. van den Heuvel, Marco Johansson, Henrik Josefsson, Bo-Göran Kristoffersson, Anna Linnanen, Tero Lisius, Annea Männikkö, Roope Nordén, Bo Price, Steve Ripa, Lena Rognan, Didier Rosendahl, Alexander Skrinjar, Marco Urbahns, Klaus Increasing Selectivity of CC Chemokine Receptor 8 Antagonists by Engineering Nondesolvation Related Interactions with the Intended and Off-Target Binding Sites 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. DMPK profile;receptor models;series;decrease compound lipophilicity;stability;steric hindrances;CCR 8 antagonists;CCR 8;Engineering Nondesolvation Related Interactions;lipophilic fragments;component analysis;CC Chemokine Receptor 8 Antagonists;compound selectivity;interaction;engineering nondesolvation;QSAR;Electrophysiological measurements;cytochrome Cyp 2D;hERG ion channel 2009-12-10
    https://acs.figshare.com/articles/journal_contribution/Increasing_Selectivity_of_CC_Chemokine_Receptor_8_Antagonists_by_Engineering_Nondesolvation_Related_Interactions_with_the_Intended_and_Off_Target_Binding_Sites/2806927
10.1021/jm900713y.s001