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. 2024 Aug 6;15(9):1491-1499.
doi: 10.1021/acsmedchemlett.4c00216. eCollection 2024 Sep 12.

Virtual Screening and Molecular Docking: Discovering Novel METTL3 Inhibitors

Junyi Yang  1   2 , Yanwen He  1   2 , Youkun Kang  1   2 , Liteng Shen  3 , Wen Zhang  1   2 , Yumeng Yan  1   2 , Xinyi Li  1   2 , Wenhai Huang  1   2 , Xiangwei Xu  1   2
Affiliations

Virtual Screening and Molecular Docking: Discovering Novel METTL3 Inhibitors

Junyi Yang et al. ACS Med Chem Lett. .

Abstract

Methyltransferase-like 3 (METTL3) is an RNA methyltransferase that catalyzes the N6 -methyladenosine (m6A) modification of mRNA in eukaryotic cells. Past studies have shown that METTL3 is highly expressed in various cancers and is closely related to tumor development. Therefore, METTL3 inhibitors have received widespread attention as effective treatments for different types of tumors. This study proposes a hybrid high-throughput virtual screening (HTVS) protocol that combines structure-based methods with geometric deep learning-based DeepDock algorithms. We identified unique skeleton inhibitors of METTL3 from our self-built internal database. Among them, compound C3 showed significant inhibitory activity on METTL3, and further molecular dynamics simulations were performed to provide more details about the binding conformation. Overall, our research demonstrates the effectiveness of hybrid virtual algorithms, which is of great significance for understanding the biological functions of METTL3 and developing treatment methods for related diseases.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) The m6A dynamic modification and related proteins. (B) Targets and biological role of METTL3–14 as promoters in different tumors (by Figdraw).
Figure 2
Figure 2
Structure and classification of inhibitors targeting METTL3.
Figure 3
Figure 3
Hybrid virtual screening workflow schematic.
Figure 4
Figure 4
Structural data of 20 selected compounds.
Figure 5
Figure 5
(A) METTL3–14 MTase-Glo assay results for 20 selected compounds. (B) Determination of the antiproliferative activity of compounds C3, C8, and STM2457 in the PC-9 and NCI-H1975 cell lines.
Figure 6
Figure 6
(A, B) Interaction between METTL3 and compound C3 before induced-fit docking and two-dimensional diagram of protein–ligand interaction. (C, D) Interaction between METTL3 and compound C3 after induced-fit docking and two-dimensional diagram of the protein–ligand interaction.
Figure 7
Figure 7
(A) Root-mean-square deviation (RMSD) values for compounds C3 and METTL3. (B) Root-mean-square fluctuation (RMSF) measurement of the mean deviation of METTL3 protein residues. (C) Contribution of compound C3–METTL3 complexes. (D) Detailed schematic of the interaction of compound C3 with METTL3 residues after induced-fit docking.
See this image and copyright information in PMC

References

    1. Sun W. J.; Li J. H.; Liu S.; Wu J.; Zhou H.; Qu L. H.; Yang J. H. RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data. Nucleic Acids Res. 2016, 44 (D1), D259–65. 10.1093/nar/gkv1036. - DOI - PMC - PubMed
    1. Yang X.; Hu X.; Liu J.; Wang R.; Zhang C.; Han F.; Chen Y.; Ma D. N6-methyladenine modification in noncoding RNAs and its function in cancer. Biomarker Res. 2020, 8 (1), 61. 10.1186/s40364-020-00244-x. - DOI - PMC - PubMed
    1. Bedi R. K.; Huang D.; Eberle S. A.; Wiedmer L.; Śledź P.; Caflisch A. Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer. ChemMedChem 2020, 15 (9), 744–748. 10.1002/cmdc.202000011. - DOI - PubMed
    1. Jia G.; Fu Y.; Zhao X.; Dai Q.; Zheng G.; Yang Y.; Yi C.; Lindahl T.; Pan T.; Yang Y. G.; He C. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 2011, 7 (12), 885–7. 10.1038/nchembio.687. - DOI - PMC - PubMed
    1. Tang C.; Klukovich R.; Peng H.; Wang Z.; Yu T.; Zhang Y.; Zheng H.; Klungland A.; Yan W. ALKBH5-dependent m6A demethylation controls splicing and stability of long 3′-UTR mRNAs in male germ cells. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (2), E325–E333. 10.1073/pnas.1717794115. - DOI - PMC - PubMed

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