Based on the Substrate Envelope Hypothesis and the available HIV-1 protease inhibitor darunavir, a new pharmacophore model of HIV-1 protease inhibitors was constructed, and applied to the Traditional Chinese Medicine Database searching. By molecular docking, two compounds of novel structure that not only bind well with the HIV-1 protease, but also fit well within the substrate envelope, were found. They were annomonicin and desacetylbufotalin. Then molecular dynamics simulations were used to study these two compounds, which were complexed with HIV-1 protease in explicit water molecules. The structural stability and binding free energies were selected to evaluate these two compounds. With the hybrid method taking advantage of the synergistic effects of structure-based and ligand-based drug design techniques, the two new compounds were selected as the candidate compounds in this work. Through theory study and analysis, annomonicin is worthy of further study and research.

Key words: substrate envelope hypothesis, pharmacophore, molecular docking, molecular dynamics simulation, HIV-1 protease inhibitor