Cation–π Interactions at the Active Site of Factor Xa: Dramatic Enhancement upon Stepwise N‐Alkylation of Ammonium Ions

Abstract

In pocket: A new class of potent inhibitors of factor Xa features a quaternary ammonium ion to fill the aromatic box in the S4 pocket and a 2-chlorothiophenyl group to occupy the S1 pocket (see picture; red O, blue N, yellow S, green Cl). Changing from a primary to a quaternary ammonium ion increases the binding affinity by a factor of 1000. The poor affinity in the former case suggests negligible cation–π interactions between Lys and Trp.