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Updated: Jan 8, 2026
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Discovery of novel selective PRMT5-MTA inhibitors through structure-based virtual screening
Ning Ma1, Yang Chen1, Yiru Liang2
1Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
Abstract:
The PRMT5-MTA complex, which is uniquely present in cancer cells with MTAP gene deletions, represents a compelling target for synthetic lethality strategies in cancer therapy. Despite the identification of PRMT5-MTA inhibitors to date, none have advanced to clinical use, and the chemical diversity among these inhibitors remains limited. Therefore, there is a pressing need for structurally novel inhibitors. Herein, we reported the discovery of new PRMT5-MTA inhibitors identified through structure-based virtual screening. Among these, Compound 14 demonstrated a binding affinity (KD) of 236 nM for the PRMT5-MTA complex, exhibiting 12.0-fold selectivity over the PRMT5-SAM complex as determined by SPR (MTA+ KD = 0.236 μM, SAM+ KD = 2.84 μM, ratio = 12.0×) and a stronger inhibitory effect on PRMT5 enzyme activity in the presence of MTA. Molecular dynamics (MD) simulations provided insights into the binding mode of Compound 14 with the PRMT5 protein, facilitating the identification of derivatives 88 and 108, thereby expanding the chemical space of hit compounds. Our findings could not only enhance the chemical diversity of PRMT5-MTA selective inhibitors, but also deepen the understanding of the structure-activity relationship (SAR) governing PRMT5 selectivity. The discovered compounds represent promising starting points for the development and optimization of novel PRMT5-MTA inhibitors.
Insights
Researchers discovered novel PRMT5-MTA inhibitors for cancer therapy. Compound 14 shows strong binding and selectivity, expanding options for developing new synthetic lethality drugs targeting cancers with MTAP deletions.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- The PRMT5-MTA complex is a unique target in cancers with MTAP gene deletions.
- Current PRMT5-MTA inhibitors lack clinical advancement and chemical diversity.
- Novel inhibitors are crucial for synthetic lethality cancer therapy.
Purpose of the Study:
- To discover structurally novel PRMT5-MTA inhibitors.
- To expand the chemical space of selective PRMT5-MTA inhibitors.
- To understand the structure-activity relationship (SAR) for PRMT5 selectivity.
Main Methods:
- Structure-based virtual screening identified initial hit compounds.
- Surface Plasmon Resonance (SPR) assessed binding affinity and selectivity.
- Molecular Dynamics (MD) simulations elucidated binding modes.
Main Results:
- Compound 14 exhibited a KD of 236 nM for PRMT5-MTA with 12.0-fold selectivity over PRMT5-SAM.
- Compound 14 demonstrated enhanced inhibition of PRMT5 activity in the presence of MTA.
- Derivatives 88 and 108 were identified, expanding the chemical scaffold.
Conclusions:
- Novel PRMT5-MTA inhibitors were discovered through structure-based virtual screening.
- The findings enhance chemical diversity and SAR understanding for PRMT5 inhibitors.
- These compounds serve as promising leads for developing new cancer therapeutics.
