Ligand screening to pre-miRNA 149 G-quadruplex investigated by molecular dynamics

Abstract

Using a molecular dynamics approach, the study of the interaction between six different known ligands and a predicted pre-miRNA 149 RNA G-quadruplex (rG4) structure is reported. The stabilization of rG4 structures formed within the pre-miRNA stem-loop regions using small ligands is an attractive anticancer strategy. Particularly, miRNA-149 is upregulated in a variety of cancers such as prostate cancer and is therefore a potential target for drug development. The results show that ligands C₈ and PhenDC₃ interact with the rG4 structure via stacking interactions with the end G-quartets. Ligands [16]phenN₂, [32]phen₂N₄ and pyridostatin on the other hand bind the loops/groove interface of the rG4 being H-bonding and electrostatic interactions the driving force of the interaction. The C₈ precursor, C₈-NH₂, emphasizes the structural nuances of the rG4 short loops as the lack of a large terminal aromatic moiety produced a mixed stacking-groove binding mode. Overall, this study may help the design of specific ligands for pre-miRNA rG4 towards anticancer therapeutics development.

Communicated by Ramaswamy H. Sarma

Keywords:

• miRNA 149
• RNA G-quadruplex
• molecular dynamics
• ligand screening
• thermodynamics

Acknowledgements

The authors acknowledge Jean-Louis Mergny for the valuable discussion and suggestions.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

J. Carvalho acknowledges a doctoral fellowship grant from the FCT – Foundation for Science and Technology ref. SFRH/BD/122953/2016. T. Santos also acknowledges FCT for the doctoral fellowship PD/BD/142851/2018 integrated in the Ph.D. Programme in NMR applied to chemistry, materials and biosciences (PD/00065/2013). This work was supported by project ‘Ações Integradas Luso-Francesas’ ref. TC-15/17, Project ‘Programa Pessoa’ ref. 5079/2019, FCT project ref. IF/00959/2015 financed by Fundo Social Europeu and Programa Operacional Potencial Humano, FCT project ref. UID/Multi/04349/2013, project Fundação Luso-Americana (FLAD) Healthcare 2020 ref. 45/2018, MIT Portugal FCT project BIODEVICE ref. MIT-EXPL/BIO/0008/2017 and UTAustin Portugal Program Exploratory project DREAM ref. UTAP-EXPL/NTec/0015/2017. This work was also supported by POCI – COMPETE 2020 – Operational Programme Competitiveness and Internationalisation in Axis I – Strengthening research, technological development and innovation (project POCI-01-0145-FEDER-007491).