Tuning Stacking Interactions between Asp–Arg Salt Bridges and Heterocyclic Drug Fragments

Stacking interactions can play an integral role in the strength and selectivity of protein–drug binding and are of particular interest given the ubiquity and variety of heterocyclic fragments in drugs. In addition to traditional stacking interactions between aromatic rings, stacking interactions involving heterocyclic drug fragments and protein salt bridges have also been observed. These “salt-bridge stacking interactions” can be quite strong but are not well understood. We studied stacked dimers of the acetate···guanidinium ion pair with a diverse set of 63 heterocycles using robust ab initio methods. The computed interaction energies span more than 10 kcal mol–1, indicating the sensitivity of these salt-bridge stacking interactions to heterocycle features. Trends in both the strength and preferred geometry of these interactions can be understood through analyses of the electrostatic potentials and electric fields above the heterocycles. We have developed new heterocycle descriptors that quantify these effects and used them to create robust predictors of the strength of salt-bridge stacking interactions both in the gas phase and a protein-like dielectric environment. These predictive tools, combined with a set of qualitative guidelines, should facilitate the choice of heterocycles that maximize salt-bridge stacking interactions in drug binding sites.