ci9b00395_si_001.pdf (985.92 kB)
Hydration of Aromatic Heterocycles as an Adversary of π‑Stacking
journal contribution
posted on 2019-10-17, 13:38 authored by Johannes
R. Loeffler, Michael Schauperl, Klaus R. LiedlHydration is one of the key players
in the protein–ligand
binding process. It not only influences the binding process per se, but also the drug’s absorption, distribution,
metabolism, and excretion properties. To gain insights into the hydration
of aromatic cores, the solvation thermodynamics of 40 aromatic mono-
and bicyclic systems, frequently occurring in medicinal chemistry,
are investigated. Thermodynamics is analyzed with two different methods:
grid inhomogeneous solvation theory (GIST) and thermodynamic integration
(TI). Our results agree well with previously published experimental
and computational solvation free energies. The influence of adding
heteroatoms to aromatic systems and how the position of these heteroatoms
impacts the compound’s interactions with water is studied.
The solvation free energies of these heteroaromatics are highly correlated
to their gas phase interaction energies with benzene: compounds showing
a high interaction energy also have a high solvation free energy value.
Therefore, replacing a compound with one having a higher gas phase
interaction energy might not result in the expected improvement in
affinity. The desolvation costs counteract the higher stacking interactions,
hence weakening or even inverting the expected gain in binding free
energy.