Molecular Docking-assisted Protein Chip Screening of Inhibitors for Bcl-2 Family Protein-protein Interaction to Discover Anticancer Agents by Fragment-based Approach

For fragment-based cancer drug discovery, we introduced a molecular docking simulation combined with a protein chip assay. Protein chip technology was used to find fragment-hits that had inhibitory activity against Bcl-2 protein from 131 pre-selected fragment chemicals. Molecular docking simulation was performed for the 12 identified fragment-hits to establish the binding mode of these compounds in the Bcl-2 site. Using the molecular docking-assisted protein chip screening system, we derived a virtual compound structure with an important scaffold feature for interaction with the Bcl-2 protein. We then tested the anticancer activity of 26 compounds that were similar to the scaffold structure. The anticancer activity was confirmed by MTT-assay in A549 lung cancer cells. Finally, three chemicals showed dose-dependent inhibitory activity against cancer cell proliferation. We suggest that the present molecular docking-assisted protein chip assay can be used as a platform technology in the fragment-based drug development process to discover inhibitory agents of protein-protein interactions.