Binding affinity scoring function penalizing compounds which make unfavorable hydrophobic contacts with localized water molecules in the receptor active site

A method of scoring binding affinity of a proposed ligand molecule for a receptor molecule using a sufficiently programmed computer for the following steps:

• a. obtaining computer stored data representing a predicted ligand-receptor structure,
• b. determining whether the receptor alone, without a docked ligand, includes one or more hydration sites occupied by localized water, and, if so,
• c. determining if after docking a receptor-localized water interacts with a hydrophobic ligand atom, and if the docking of the ligand into the receptor results in unfavorable interaction of the ligand with a localized water molecule occupying a receptor hydration site,
• d. determining whether one or more of the exceptions conditions i.-iv. is present:
• i. the hydrophobic ligand atom has a net positively charged ligand atom positioned a distance of 4 atoms or fewer from the hydrophobic ligand atom, where the distance is determined by bond connectivity of the atoms in the ligand;
• ii. the hydrophobic ligand atom that is part of a ligand —CH3 group, or a ligand atom within 3 atoms of a —CH3 group, where the localized water borders the edge of a hydrophobic pocket giving it access to surrounding water;
• iii. the localized receptor water is positioned within 5 Å of a positively charged ligand atom;
• iv. the localized receptor water has hydrogen bonds to the ligand;
• e. applying a penalty to scoring function of binding affinity if 1) the localized receptor water interacts with a hydrophobic ligand atom as determined in step c, and 2) none of the exception conditions i. iv. is present.