2. Academic Validation
  3. Discovery of the selective chemical probe for protein methyltransferase METTL13 by biological evaluation and molecular dynamics simulation

Discovery of the selective chemical probe for protein methyltransferase METTL13 by biological evaluation and molecular dynamics simulation

  • Bioorg Chem. 2026 Feb:169:109426. doi: 10.1016/j.bioorg.2025.109426.
Meiling Zhang 1,  Qingqing Yu 1,  Bing Zhang 2,  Huiying Zhu 1,  Jingwen Sun 3,  Shijia Xiao 1,  Kexin Yan 1,  Dayang Yan 1,  Yuhong Qin 1,  Chen Xi 1,  Lulu Wang 3,  Cheng Dong 4,  Ying Ma 5,  Dongxing Chen 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
  • 2 Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 3 Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, State Key laboratory of Experimental Hematology, Department of Chemical Biology, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
  • 4 Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
  • 6 Department of Medicinal Chemistry, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
PMID: 41468753 DOI: 10.1016/j.bioorg.2025.109426
Abstract

METTL13, a dual-functional methyltransferase harboring protein N-terminal methyltransferase (NTMT) activity, has emerged as a pivotal regulator in carcinogenesis, tumor progression, and patient prognosis, thereby garnering substantial interest as a promising therapeutic target for cancers. Despite its clinical significance, no specific chemical probes or inhibitors have been reported to date, highlighting an urgent need for drug discovery efforts targeting this enzyme. Herein, we employed the bisubstrate inhibitor strategy to develop the chemical probe NT32 for METTL13, which showed selective against a panel of methyltransferases. Comprehensive investigations into the structural and functional impacts of NT32 on METTL13 were conducted via molecular docking, molecular dynamics (MD) simulations, and multi-dimensional analyses. Computational modeling revealed that NT32 could occupy both the SAM/SAH-binding pocket and the peptide substrate-binding site of METTL13 simultaneously, establishing a bivalent binding mode. Notably, MD simulations unveiled significant enhancements in both positive and negative residue correlations within the NT32-METTL13 complex compared to the wild-type enzyme. Specifically, interactions between NT32 and critical residues (Gly503, Asn614, Gly644, Glu645) strengthened the connectivity of Met692 with its surrounding residues. This structural reorganization was accompanied by augmented correlated motions between the Gly501-Val511 region (loop501-504-α2505-511) and the Leu613-Leu620 segment (β5613-615-loop616-618-α6619-620), culminating in a more compact and stable protein conformation. Furthermore, NT32 specifically targeted and stabilized METTL13 in cellular thermal shift assay. These findings not only provide mechanistic insights into NT32-METTL13 interactions but also pave the way for discovery of METTL13 probes or inhibitors.

Keywords

Bisubstrate analogs; Chemical probe; MD simulation; METTL13.

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