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In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

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Abstract

G-quadruplex DNA formed in NHEIII1 region of oncogene promoter inhibits transcription of the genes. In this study, virtual screening combining pharmacophore-based search and structure-based docking screening was conducted to discover ligands binding to G-quadruplex in promoter region of c-MYC. Several hit ligands showed the selective PCR-arresting effects for oligonucleotide containing c-MYC G-quadruplex forming sequence. Among them, three hits selectively inhibited cell proliferation and decreased c-MYC mRNA level in Ramos cells, where NHEIII1 is included in translocated c-MYC gene for overexpression. Promoter assay using two kinds of constructs with wild-type and mutant sequences showed that interaction of these ligands with the G-quadruplex resulted in turning-off of the reporter gene. In conclusion, combined virtual screening methods were successfully used for discovery of selective c-MYC promoter G-quadruplex binders with anticancer activity.

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Acknowledgments

This study was supported by Basic Science Research Program [2010-0029358] through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology; the Korea Healthcare technology R&D Project [A092006], Ministry for Health & Welfare.

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Authors and Affiliations

  1. School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, South Korea

    Hyun-Jin Kang & Hyun-Ju Park

  2. College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA

    Hyun-Jin Kang

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  1. Hyun-Jin Kang
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  2. Hyun-Ju Park
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Correspondence to Hyun-Ju Park.

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Kang, HJ., Park, HJ. In silico identification of novel ligands for G-quadruplex in the c-MYC promoter. J Comput Aided Mol Des 29, 339–348 (2015). https://doi.org/10.1007/s10822-014-9826-z

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  • DOI: https://doi.org/10.1007/s10822-014-9826-z

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