Lysine sulfonamide and its structural analogs, a class of Human Immunodeficiency Virus protease inhibitors has gained importance in recent years due to its mode of action. QSAR analysis for multiple ligand-receptor complexes can be performed using binding interaction energies derived from the molecular dynamics simulations. A Receptor-dependent QSAR (RD-QSAR) analysis was carried out for 65 lysine sulfonamide analogs complexed with HIV-protease using Prime Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method. The lysine sulfonamide analogs were docked in the receptor active site and the obtained complexes were further rescored using Prime MM-GBSA method. The descriptors, docking score and MM-GBSA free energy of binding were used to derive a relationship with biological inhibition constant. The influence of individual free energy components on biological activity and the effect of structural flexibility (in terms of strain energies) over the prediction model has been studied using two models (with and without strain energy), built using forward entry MLR method. Inclusion of strain energies enhanced the effect of all the free energy of binding components and hence reflects their importance. The statistical significance of the derived QSAR models was described using the parameters, r², F-test and RMSE. A test set of 11 compounds was used to ensure the predictability of the models (q² cv, PRESS). Results from this study would be useful in identifying anti-virals with energetically favorable interactions.