The scaffold is aligned well for all the compounds in their initial structures; it has the same pose as shown in Figure . For the compounds with similar experimental binding affinities, the free energies of the charged ones are more favourably predicted than the electrostatically neutral ones (Figure ). A good correlation is obtained for the charged compounds, with a correlation coefficient of 0.84. This is largely due to the correct predictions of the ranking for the two compounds with less favourable binding affinities (Figure ). The correlation coefficient exhibits no improvements when the charged compounds are excluded, having the same correlation coefficient of 0.33 but a reduced covariance from 1.37 to 1.11 kcal/mol. The weak correlation is due to the wide spread of the predictions for the compounds with less favourable binding affinities. More negative predictions are made for some of these compounds (Figure ), which are caused by more negative van der Waals contributions. Based on the positions and the chemical properties of the modifications made to the scaffold (Figure , Table ), the compounds are clustered into different groups. The grouping is based on the following categories: (1) ether variations, (2) pyridyl variation, (3) central aryl variation, (4) lactam substituent variation, (5) central aryl and lactam, (6) central aryl and lactam and ethers (Figure ). The subgroup within category 6 shows a moderate correlation (r= 0.52), while the subgroup with the combination of 1 and 6 (subgroup 16) manifests a strong correlation (r=0.66). The combination of the two subgroups, containing about half of the neutral compounds, yields a similar correlation to that for subgroup 16. The other subgroups show weak or very weak correlations/anticorrelations (Figure , Table ).