title: Search for novel remedies to augment radiation resistance of inhabitants of Fukushima and Chernobyl disasters: identifying DNA repair protein XRCC4 inhibitors.
abstract: Two nuclear plant disasters occurring within a span of 25 years threaten health and genome integrity both in Fukushima and Chernobyl. Search for remedies capable of enhancing DNA repair efficiency and radiation resistance in humans appears to be a urgent problem for now. XRCC4 is an important enhancer in promoting repair pathway triggered by DNA double-strand break (DSB). In the context of radiation therapy, active XRCC4 could reduce DSB-mediated apoptotic effect on cancer cells. Hence, developing XRCC4 inhibitors could possibly enhance radiotherapy outcomes. In this study, we screened traditional Chinese medicine (TCM) database, TCM Database@Taiwan, and have identified three potent inhibitor agents against XRCC4. Through molecular dynamics simulation, we have determined that the protein-ligand interactions were focused at Lys188 on chain A and Lys187 on chain B. Intriguingly, the hydrogen bonds for all three ligands fluctuated frequently but were held at close approximation. The pi-cation interactions and ionic interactions mediated by o-hydroxyphenyl and carboxyl functional groups respectively have been demonstrated to play critical roles in stabilizing binding conformations. Based on these results, we reported the identification of potential radiotherapy enhancers from TCM. We further characterized the key binding elements for inhibiting the XRCC4 activities.
authors.affiliation: Laboratory of Computational and Systems Biology, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Mao-Feng
authors.initials: MF
authors.lastname: Sun
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Lui
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Calvin Yu-Chian
authors.initials: CY
authors.lastname: Chen
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D047852:Chernobyl Nuclear Accident; D017076:Computer-Aided Design; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008516:Medicine, Chinese Traditional; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011836:Radiation Tolerance / Q000187:drug effects*; D011837:Radiation-Protective Agents / Q000737:chemistry* / Q000494:pharmacology; D018788:Radioactive Hazard Release
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D011837:Radiation-Protective Agents; C101467:XRCC4 protein, human