Efficient electrostatic solvation model for protein-fragment docking

A method is presented for the fast evaluation of the binding energy of a protein‐small molecule complex with electrostatic solvation. It makes use of a fast preprocessing step based on the assumption that the main contribution to electrostatic desolvation upon ligand binding originates from the displacement of the first shell of water molecules. For a rigid protein, the precomputation of the energy contributions on a set of grids allows the estimation of the energy in solution of about 300 protein‐fragment binding modes per second on a personal computer. The docking procedure is applied to five rigid binding sites whose size ranges from 17 residues to a whole protein of 107 amino acids. Using a library of 70 mainly rigid molecules, known micromolar inhibitors or close analogs are docked and prioritized correctly. The docking based rank‐ordering of the library requires about 5 h and is proposed as a complementary approach to structure‐activity relationships by nuclear magnetic resonance. Proteins 2001;42:256–268. © 2000 Wiley‐Liss, Inc.