Solvation plays an important role in ligand-protein association and has a s
trong impact on comparisons of binding energies for dissimilar molecules. W
hen databases of such molecules are screened for complementarity to recepto
rs of known structure, as often occurs in structure-based inhibitor discove
ry, failure to consider ligand solvation often leads to putative ligands th
at are too highly charged or too large. To correct for the different charge
states and sizes of the ligands, we calculated electrostatic and non-polar
solvation free energies for molecules in a widely used molecular database,
the Available Chemicals Directory (ACD). A modified Born equation treatmen
t was used to calculate the electrostatic component of Ligand solvation. Th
e non-polar component of ligand solvation was calculated based on the surfa
ce area of the ligand and parameters derived from the hydration energies of
apolar ligands, These solvation energies were subtracted from the ligand-r
eceptor interaction energies. We tested the usefulness of these corrections
by screening the ACD for molecules that complemented three proteins of kno
wn structure, using a molecular docking program. Correcting for ligand solv
ation improved the rankings of known ligands and discriminated against mole
cules with inappropriate charge states and sizes. (C) 1999 Wiley-Liss, Inc.