Full text

Turn on search term navigation

© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Uterine fibroids, though benign in nature, are burdensome tumors of the myometrium and continue to weigh heavily on the landscape of women’s health. They affect millions and yet receive a fraction of the therapeutic innovation afforded to malignant diseases. Despite their prevalence, the molecular underpinnings of fibroid pathogenesis have long been met with a blind eye in drug development. Recent insights, however, reveal G-protein-coupled receptor 10 (GPR10) as a central driver of fibroid growth, promoting cell survival through the PI3K/Akt and MAPK/ERK signaling pathways following REST repression. In this study, we present a rigorous, computationally guided approach to design small interfering RNAs (siRNAs) that silence GPR10 expression at the transcriptomic level. Beginning with a library of 275 siRNA candidates, we undertook a layered in-silico refinement process, combining thermodynamic assessment, secondary structure modeling and off-target filtration, to distill a shortlist of ten high-confidence molecules. These were subjected to structural docking against Argonaute 2, the catalytic engine of the RNA-induced silencing complex, revealing siRNA8 and siRNA12 as lead candidates distinguished by robust binding affinity, high predicted silencing efficacy, which was greater than 93.5%, and precise conformational fit. Subsequent molecular dynamics simulations under CHARMM-GUI/CHARMM36m force field, confirmed the structural stability and sustained silencing potential of the complex. Collectively, these findings identify GPR10 as a therapeutically actionable driver in fibroid biology and lay the groundwork for precision RNAi strategies targeting non-malignant, yet clinically neglected, hormone-dependent disorders.

Details

Title
Molecular dynamics simulations based siRNA design against GPR10 reveals stable RNAi therapeutics for hormone-dependent uterine fibroids
Author
Sriram, Srineevas 1 ; Palanichamy, Chandresh 1 ; Subash, P. T. 1 ; Gupta, Manshi Kumari 1 ; Sudandiradoss, C. 1 

 Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, 632014, Vellore, Tamil Nadu, India (ROR: https://ror.org/03tjsyq23) (GRID: grid.454774.1) 
Pages
31708
Section
Article
Publication year
2025
Publication date
2025
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3244651715
Copyright
© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.