HIV-1 protease is a key enzyme in the maturation process of HIV protein. HIV-1 PIs are an important class of drug used to inhibit HIV infection and have an important effect on virus replication. In this article, 3D-QSAR was used to investigate the molecular simulations related to 50 DRV selective inhibitors. A 3D-QSAR model was established based on CoMFA and CoMSIA, and the best CoMSIA field was selected based on the model prediction results. The results showed that the CoMFA model (q² = 0.809, r² = 0.989) and CoMSIA (S + E + D + H (q² = 0.834, r² = 0.988)) have an excellent prediction capability. In addition, the method of docking between template molecules and the receptor was studied by molecular docking, and the results of the 3D-QSAR model were further verified. Through the analysis of counter maps, we designed 9 new small molecules and predicted their activity. Afterward, the newly designed small molecules were docked, and MD simulations and binding free energies were used to verify the accuracy of the docking results. Via a series of predictions, it was concluded that the newly designed compound D08 may have a better inhibitory activity. Furthermore, for the novel molecules, their ADMET properties and drug likeness were also analysed. The results show that these novel molecules also have reasonable pharmacokinetics. These results may provide an important reference for the design and development of novel effective HIV-1 PR inhibitors.