A new linear interaction energy (LIE) method based on a continuum solvent surface generalized Born (SGB) model is proposed for protein−ligand binding affinity calculations. The new method SGB-LIE is about 1 order of magnitude faster than previously published LIE methods based on explicit solvents. It has been applied to several binding sets: HEPT analogues binding to HIV-1 reverse transcriptase (20 ligands), sulfonamide inhibitors binding to human thrombin (seven ligands), and various ligands binding to coagulation factor Xa (eight ligands). The SGB-LIE predictions and cross-validation results show that about 1.0 kcal/mol accuracy is achievable for binding sets with as many as 20 ligands, e.g., for the HIV-1RT binding set, RMS errors of 1.07 and 1.20 kcal/mol are achieved for LIE fitting and leave-one-out cross validation, respectively, with correlation coefficients r2 equal to 0.774 and 0.717. We have also explored various techniques for the LIE underlying conformation space sampling, including molecula...