and two indices and EC scores are calculated in Table . It is evident that ligands 44, 47, 49, 50, 52, and 54 meet the criteria that esp_extre is larger than 20 kcal/(mol*e) and sas_ratio is smaller than 0.35. We plotted the data of these ligands and a strong linear correlation of EC scores and activity obtained (Figure ). The R 2 coefficient improved from 0.01 (when whole list of compounds plotted) to 0.71 (compound list meet the criteria of esp_extre and sas_ratio). In the second case, 5UVX and 5UVY were as the targets. The ligands used in this study and calculated data are summarized in Table and Figure . Almost all small molecules are well wrapped in the protein pockets because their sas_ratio indexes are much smaller than 0.35. Except for ligand 27, the rest sas_ratio indexes are even no more than 0.15. The pocket is also proved to be able to have strong electrostatic interaction with ligands because of high esp_extre values (larger than 20). Although these two indices meet our criterion, however, the EC scores have even opposite relationship with Ki. As shown in Figure , the R 2 coefficient is -0.30 where minus sign only represents the opposite trend. There are water bridges connect ligand and protein in the crystal structure. Since we fixed the atomic position of water and protein during docking process, the hydrogen bonding interaction between ligand and water is poor modeled. Thus, the strength of such hydrogen bonding is not well described. It is also possible that different ligands need different number of bridge water which will influence the system entropy. Apparently, entropy contribution cannot be estimated by EC score neither can esp_extre or sas_ratio indices. To show the importance of these bridge water molecules, we tried to remove all the crystal water molecules and recalculated the EC scores. The result got even worse (yielding a -0.40 R 2 coefficient). This case shows one aspect limitation of esp_extre and sas_ratio indices that additional factors or indices should be exquisitely proposed to limit EC score in a more confident application range.