Comparative Study of the Crystal Structure and Simulated 3D Structure of the Hsp90^N-Inhibitor Complex

The crystal structure of a target-ligand plays an indispensable role in rational drug design, structural optimization, and understanding the molecular interaction mechanism. For drug targets without crystal structures, the simulated 3D structure will provide an alternative important reference. However, the credibility of the simulated structure and its difference from the real crystal structure deserve deep consideration. The complex crystal structures of the target Hsp90(N) and its four small molecular inhibitors has previously been successfully determined. Herein, computer-aided molecular docking technology is applied to predict complex 3D structures, and the comparison between the simulated 3D structures and crystal structures is analyzed. Compared with the complex crystal structures, the simulated 3D structures of the four groups have higher consistency with the main chains, whereas the branch chains, binding modes of inhibitors, and molecular interactions are different in detail. Thus, the simulated 3D complex structure can provide useful information to guide drug design and structural optimization of inhibitors when the crystal structure is missing, but it cannot replace the crystal structure and should be used with caution.