Molecular Docking-assisted Protein Chip Screening of Inhibitors for Bcl-2 Family Protein-protein Interaction to Discover
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Original Article
Molecular Docking-assisted Protein Chip Screening of Inhibitors for Bcl-2 Family Protein-protein Interaction to Discover Anticancer Agents by Fragment-based Approach Myoung-Schook Yoou1, Sungjoon Cho2 & Youngjin Choi
2,3,
*
Received: 17 February, 2019 / Accepted: 4 June, 2019 / Published online: 22 July, 2019 â’¸The Korean BioChip Society and Springer 2019
Abstract 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. Keywords: Anticancer agents, Docking simulation, Drug screening, Molecular modelling, Protein chip 1 Department of Biomedical Laboratory, Korea Nazarene University, Cheonan, 31172, Republic of Korea 2 School of Food and Pharmaceutical Engineering, Hoseo University, Asan 31499, Republic of Korea 3 Research Institute for Basic Science & BioChip Research Center, Hoseo University, Asan 31499, Republic of Korea *Correspondence and requests for materials should be addressed to Y. Choi ( [email protected])
Introduction In the history of cancer treatment, traditional chemotherapy involved administering chemicals without distinguishing normal cells from cancer cells. Current cancer therapies have been developed as target-directed approaches based on molecular and cellular mechanisms1. A family of kinases is a representative example of the molecular target for the developing a cancer drug2. Imatinib, a Bcr-Abl kinase inhibitor, has been used clinically to treat chronic myelogenous leukemia3. Gefitinib and erlotinib were developed to inhibit biological dysfunction of epidermal growth factor receptor in lung cancer4,5. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, was introduced to treat colorectal cancer6. These treatments each focus on blocking the function of specific proteins that have a major impact on cancer progression. As a sophisticated strategy for targeted cancer therapy, the modulation of a proteinprotein interaction (PPI) has gained attention for providing promising therapeutic targets7. A PPI drug is described as any chemica
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