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VOLUME 14 , ISSUE 2 ( July-December, 2024 ) > List of Articles

Original Article

Molecular Characterization and Potential Inhibitors Prediction of Protein Arginine Methyltransferase-2 in Carcinoma: An Insight from Molecular Docking, ADMET Profiling and Molecular Dynamics Simulation Studies

Md Sahadot Hossen, Md Nur Islam, Md Enayet Ali Pramanik, Md Hasanur Rahman, Md Al Amin, Saraban T Antora, Farzana S Sraboni, Rifah N Chowdhury, Nazia Farha, Amina A Sathi, Samia Sadaf, Farjana Banna, Md Rezaul Karim, Nasrin Akter, Md Royhan Gofur, Md Shariful Islam, M Morsed Z Miah, Mira Akhter, Md Sharif Hasan, Fahmida Fahmin, Mohammad M Rahman, Prabir M Basak, Amio K Sonnyashi, Haimanti S Das, Mamun Al Mahtab, Sheikh MF Akbar

Keywords : Computer-aided drug design, Homology modeling, Inhibitor's prediction, Molecular docking, Molecular dynamics simulation, Protein arginine methyltransferase 2

Citation Information : Hossen MS, Islam MN, Pramanik ME, Rahman MH, Amin MA, Antora ST, Sraboni FS, Chowdhury RN, Farha N, Sathi AA, Sadaf S, Banna F, Karim MR, Akter N, Gofur MR, Islam MS, Miah MM, Akhter M, Hasan MS, Fahmin F, Rahman MM, Basak PM, Sonnyashi AK, Das HS, Mahtab MA, Akbar SM. Molecular Characterization and Potential Inhibitors Prediction of Protein Arginine Methyltransferase-2 in Carcinoma: An Insight from Molecular Docking, ADMET Profiling and Molecular Dynamics Simulation Studies. Euroasian J Hepatogastroenterol 2024; 14 (2):160-171.

DOI: 10.5005/jp-journals-10018-1443

License: CC BY-NC 4.0

Published Online: 27-12-2024

Copyright Statement:  Copyright © 2024; The Author(s).


Abstract

Objectives: To predict and characterize the three-dimensional (3D) structure of protein arginine methyltransferase 2 (PRMT2) using homology modeling, besides, the identification of potent inhibitors for enhanced comprehension of the biological function of this protein arginine methyltransferase (PRMT) family protein in carcinogenesis. Materials and methods: An in silico method was employed to predict and characterize the three-dimensional structure. The bulk of PRMTs in the PDB shares just a structurally conserved catalytic core domain. Consequently, it was determined that ligand compounds may be the source of co-crystallized complexes containing additional PRMTs. Possible PRMT2 inhibitor compounds are found by using S-adenosyl methionine (SAM), a methyl group donor, as a positive control. Results: Protein arginine methyltransferases are associated with a range of physiological processes, including as splicing, proliferation, regulation of the cell cycle, differentiation, and signaling of DNA damage. These functional capacities are also related to carcinogenesis and metastasis-several forms of PRMT have been cited in the literature. These include PRMT-1, PRMT-2, and PRMT-5. Among these, the role of PRMT-2 has been shown in breast cancer and hepatocellular carcinoma. To gain more insights into the role of PRMT2 in cancer pathogenesis, we opted to characterize tertiary structure utilizing an in silico approach. The majority of PRMTs in the PDB have a structurally conserved catalytic core domain. Thus, ligand compounds were identified as a possible source of co-crystallized complexes of other PRMTs. The SAM, a methyl group donor, is used as a positive control in order to identify potential inhibitor compounds of PRMT2 by the virtual screening method. We hypothesized that an inhibitor for other PRMTs could alter PRMT2 activities. Out of 45 inhibitor compounds, we ultimately identified three potential inhibitor compounds based on the results of the pharmacokinetics and binding affinity studies. These compounds are identified as 3BQ (PubChem CID: 77620540), 6DX (PubChem CID: 124222721), and TDU (PubChem CID: 53346504). Their binding affinities are −8.5 kcal/mol, −8.1 kcal/mol, and −8.8 kcal/mol, respectively. These compounds will be further investigated to determine the binding stability and compactness using molecular dynamics simulations on a 100 ns time scale. In vitro and in vivo studies may be conducted with these three compounds, and we think that focusing on them might lead to the creation of a PRMT2 inhibitor. Conclusion: Three strong inhibitory compounds that were non-carcinogenic also have drug-like properties. By using desirable parameters in root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), molecular surface area (MolSA), and intermolecular hydrogen bonding, complexes verified structural stability and compactness over the 100 ns time frame.

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