Comparative binding energy (COMBINE) analysis method is one of the QSAR techniques for the prediction of biological activities of inhibitors based on interaction energies between ligands and proteins decomposed into each amino acid residue. We supposed that the predictive ability of the COMBINE method does not depend essentially on the molecular frameworks of ligands. To verify this idea, we performed the COMBINE analysis of non-peptide inhibitors of HIV-1 protease (HIVp), where the prediction model was constructed using inhibitors with a peptide scaffold as a training set. The predictive performance of the AMBER and CHARMm force fields was very high and at the same level (q(2)=0.75, 0.67, SDEP(cv)=0.76, 0.89, and SDEP(ex)=0.92, 0.66, respectively). The high predictive ability of the COMBINE method for the distinct scaffold compounds is due to the informative description of the interaction energies for compounds that are located at the binding site. This result suggests that COMBINE analysis may be applied not only to the lead optimization stage but also to the lead evolution stages.