Ligand solvation in molecular docking

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.