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Multi-dimensional structural footprint identification for the design of potential scaffolds targeting METTL3 in cancer treatment from natural compounds

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Abstract

Context

\({N}^{6}\)-adenosine-methyltransferase (METTL3) is the catalytic domain of the ‘writer’ proteins which is involved in the post modifications of \({N}^{6}\)-methyladinosine (\({m}^{6}A\)). Though its activities are essential in many biological processes, it has been implicated in several types of cancer. Thus, drug developers and researchers are relentlessly in search of small molecule inhibitors that can ameliorate the oncogenic activities of METTL3. Currently, STM2457 is a potent, highly selective inhibitor of METTL3 but is yet to be approved.

Methods

In this study, we employed structure-based virtual screening through consensus docking by using AutoDock Vina in PyRx interface and Glide virtual screening workflow of Schrodinger Glide. Thermodynamics via MM-PBSA calculations was further used to rank the compounds based on their total free binding energies. All atom molecular dynamics simulations were performed using AMBER 18 package. FF14SB force fields and Antechamber were used to parameterize the protein and compounds respectively. Post analysis of generated trajectories was analyzed with CPPTRAJ and PTRAJ modules incorporated in the AMBER package while Discovery studio and UCSF Chimera were used for visualization, and origin data tool used to plot all graphs.

Results

Three compounds with total free binding energies higher than STM2457 were selected for extended molecular dynamics simulations. The compounds, SANCDB0370, SANCDB0867, and SANCDB1033, exhibited stability and deeper penetration into the hydrophobic core of the protein. They engaged in relatively stronger intermolecular interactions involving hydrogen bonds with resultant increase in stability, reduced flexibility, and decrease in the surface area of the protein available for solvent interactions suggesting an induced folding of the catalytic domain. Furthermore, in silico pharmacokinetics and physicochemical analysis of the compounds revealed good properties suggesting these compounds could serve as promising MEETL3 entry inhibitors upon modifications and optimizations as presented by natural compounds. Further biochemical testing and experimentations would aid in the discovery of effective inhibitors against the berserk activities of METTL3.

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Acknowledgements

The authors would like to acknowledge the financial support through Researcher Supporting Project (project no. RSPD-2023/R672), King Saud University, Riyadh, Saudi Arabia.

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Authors and Affiliations

  1. Molecular Bio-Computation and Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa

    Abdul Rashid Issahaku, Samukelisiwe Minenhle Mncube, Clement Agoni, Mahmoud A. A. Ibrahim, Opeyemi Soremekun & Mahmoud E. S. Soliman

  2. West African Centre for Computational Research and Innovation, West Africa, Ghana

    Abdul Rashid Issahaku & Clement Agoni

  3. West African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, LG54, Accra, Ghana

    Samuel K. Kwofie

  4. Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, 7149, Saudi Arabia

    Mohamed Issa Alahmdi

  5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tabuk University, Tabuk, 71491, Saudi Arabia

    Nader E. Abo-Dya

  6. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt

    Nader E. Abo-Dya

  7. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt

    Peter A. Sidhom

  8. Chemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia

    Ahmed M. Tawfeek

  9. Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt

    Mahmoud A. A. Ibrahim

  10. Department of Physiotherapy School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa

    Namutula Mukelabai

  11. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, England

    Opeyemi Soremekun

Authors
  1. Abdul Rashid Issahaku
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  2. Samukelisiwe Minenhle Mncube
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  6. Nader E. Abo-Dya
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  10. Namutula Mukelabai
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  12. Mahmoud E. S. Soliman
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Contributions

Abdul Rashid Issahaku conceptualized and designed the study. Samukelisiwe Minenhle Mncube, Clement Agoni, and Samuel K. Kwofie interpreted data. Mohamed Issa Alahmdi, Nader E. Abo-Dya, Peter A. Sidhom, and Ahmed M. Tawfeek prepared all figures in the manuscript. Mahmoud A. A. Ibrahim, Namutula Mukelabai, and Opeyemi Soremekun wrote the manuscript. Mahmoud E.S. Soliman supervised the study. All authors reviewed the manuscript.

Corresponding author

Correspondence to Mahmoud E. S. Soliman.

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Issahaku, A.R., Mncube, S.M., Agoni, C. et al. Multi-dimensional structural footprint identification for the design of potential scaffolds targeting METTL3 in cancer treatment from natural compounds. J Mol Model 29, 122 (2023). https://doi.org/10.1007/s00894-023-05516-5

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