Probing the\nHistamine H<sub>1</sub> Receptor Binding\nSite to Explore Ligand Binding Kinetics

Analysis of structure-kinetic relationships (SKR) can\ncontribute\nto an improved understanding of receptor–ligand interactions.\nHere, fragment <b>1</b> (4-(2-benzylphenoxy)-1-methylpiperidine)\nwas used in different fragment growing approaches to mimic the putative\nbinding mode of the long residence time (RT) ligands olopatadine,\nacrivastine, and levocetirizine at the histamine H<sub>1</sub> receptor\n(H<sub>1</sub>R). SKR analyses reveal that introduction of a carboxylic\nacid moiety can increase RT at H<sub>1</sub>R up to 11-fold. Ligand\nefficiency (LE) decreases upon the introduction of the negatively\ncharged group, whereas kinetic efficiency (KE) increases up to 8.5-fold.\nThe olopatadine/acrivastine mimics give up to 15-fold differences\nin the RT, while the levocetirizine mimics afford similar RTs with\nonly a 3-fold difference. Therefore, the levocetirizine mimics are\nless sensitive to structural changes. This study illustrates that\nfor H<sub>1</sub>R, there are several ways to increase RT but the\ndifferent strategies differ significantly in SKR.