A method of scoring binding affinity of a proposed ligand molecule for a receptor molecule, which is a protein, using a computer and computer databases, the method comprises, a. obtaining computer stored data representing a predicted ligand-receptor structure, b. scoring ligand binding affinity by computerized operations which include: - determining whether the receptor includes one or more hydration sites occupied by localized water, and, if so, - determining if after docking a localized water interacts with a hydrophobic ligand atom, and if the docking the ligand into the receptor results in unfavorable interaction of the ligand with a localized water molecule occupying a receptor hydration site after docking, wherein the unfavorable interaction includes a greater increase in free energy compared to interaction of the ligand with a water molecule in bulk fluid, - determining whether one or more of the exceptions conditions i. - iv. is present: i. the hydrophobic ligand atom having a net positively charged ligand atom 4 atoms or closer to it based on bond connectivity of the atoms in the ligand; ii. the hydrophobic ligand atom is not 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 water within a hydration site is within 5Å of a positively charged ligand atom; iv. the localized water within a hydration site has hydrogen bonds to the ligand; - applying a penalty to a scoring function of binding affinity if 1) the localized water interacts with a hydrophobic ligand atom as determined in step b, and 2) none of the exception conditions i. - iv. is present. a. obtaining computer stored data representing a predicted ligand-receptor structure, b. scoring ligand binding affinity by computerized operations which include: - determining whether the receptor includes one or more hydration sites occupied by localized water, and, if so, - determining if after docking a localized water interacts with a hydrophobic ligand atom, and if the docking the ligand into the receptor results in unfavorable interaction of the ligand with a localized water molecule occupying a receptor hydration site after docking, wherein the unfavorable interaction includes a greater increase in free energy compared to interaction of the ligand with a water molecule in bulk fluid, - determining whether one or more of the exceptions conditions i. - iv. is present: i. the hydrophobic ligand atom having a net positively charged ligand atom 4 atoms or closer to it based on bond connectivity of the atoms in the ligand; ii. the hydrophobic ligand atom is not 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 water within a hydration site is within 5Å of a positively charged ligand atom; iv. the localized water within a hydration site has hydrogen bonds to the ligand; - applying a penalty to a scoring function of binding affinity if 1) the localized water interacts with a hydrophobic ligand atom as determined in step b, and 2) none of the exception conditions i. - iv. is present. - determining whether the receptor includes one or more hydration sites occupied by localized water, and, if so, - determining if after docking a localized water interacts with a hydrophobic ligand atom, and if the docking the ligand into the receptor results in unfavorable interaction of the ligand with a localized water molecule occupying a receptor hydration site after docking, wherein the unfavorable interaction includes a greater increase in free energy compared to interaction of the ligand with a water molecule in bulk fluid, if after docking a localized water interacts with a hydrophobic ligand atom, and if the docking the ligand into the receptor results in unfavorable interaction of the ligand with a localized water molecule occupying a receptor hydration site after docking, wherein the unfavorable interaction includes a greater increase in free energy compared to interaction of the ligand with a water molecule in bulk fluid, - determining whether one or more of the exceptions conditions i. - iv. is present: i. the hydrophobic ligand atom having a net positively charged ligand atom 4 atoms or closer to it based on bond connectivity of the atoms in the ligand; ii. the hydrophobic ligand atom is not 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 water within a hydration site is within 5Å of a positively charged ligand atom; iv. the localized water within a hydration site has hydrogen bonds to the ligand; i. the hydrophobic ligand atom having a net positively charged ligand atom 4 atoms or closer to it based on bond connectivity of the atoms in the ligand; ii. the hydrophobic ligand atom is not 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 water within a hydration site is within 5Å of a positively charged ligand atom; iv. the localized water within a hydration site has hydrogen bonds to the ligand; - applying a penalty to a scoring function of binding affinity if 1) the localized water interacts with a hydrophobic ligand atom as determined in step b, and 2) none of the exception conditions i. - iv. is present.