The chemokine receptor CCR5 is a main and necessary co-receptor for which HIV can recognize and enter the cells, and has been identified as a potential new target for the design of new anti-HIV therapeutic drugs. Highly active CCR5 inhibitors can prevent HIV-1 from entering target cells and block the process of infection. In this study, HQSAR and Topomer CoMFA methods were used to establish QSAR models for 75 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives, and cross-validation and non-cross-validation were performed on the generated models. Two models with good statistical parameters and reliable prediction capabilities are obtained: (Topomer CoMFA: q² = 0.687, r² = 0.868, r²_pred = 0.623; HQSAR: q² = 0.781, r² = 0.921, r²_pred = 0.636). Contour maps and color code maps provide a lot of useful information for determining structural requirements that affect activity. Topomer search technology was used for virtual screening and molecular design. Surfex-dock method and ADMET technology were used to conduct molecular docking, oral bioavailability and toxicity prediction of the designed drug molecules. Results showed that A/ASN425, A/GLY198 and A/TRP427 may be the potential active residues of CCR5 inhibitors evaluated in this study, with 40 newly designed 1-(3,3-diphenylpropyl)-piperidinyl and urea derivatives which have the main ADMET properties and can be used as a reliable anti-HIV inhibitor. These results provide a certain theoretical basis for the experimental verification of new compounds in the future.