Related Experiment Video

Updated: Jul 12, 2025

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product

Nisarg Rana1, Dhaval Patel2, Meet Parmar2

  • 1Department of Chemistry, School of Energy Technology, Pandit Deendayal Energy University, Gandhinagar, 382426, India.

Scientific Reports
|October 23, 2023
PubMed

Insights

Researchers identified novel compounds targeting the MTHFD2 enzyme

Area of Science:

  • Biochemistry
  • Computational Chemistry
  • Drug Discovery

Background:

  • Breast cancer is a leading cause of death in women globally.
  • Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is overexpressed in breast cancer and presents a druggable target.
  • Allosteric site targeting offers a strategy to overcome drug resistance.

Purpose of the Study:

  • To identify potential inhibitors targeting the allosteric site of MTHFD2.
  • To explore natural products as candidates for MTHFD2 inhibition.
  • To investigate the binding mechanisms and stability of potential inhibitors.

Main Methods:

  • Structure-based modeling and pharmacophore modeling were employed.
  • Molecular docking, HYDE assessment, and ADMET predictions were performed.
  • Molecular dynamics simulations, free-energy calculations, MM-PBSA, PCA, and FEL analysis were conducted.

Main Results:

  • Seven candidate compounds demonstrated stable behavior in simulations.
  • Six compounds exhibited tight binding to the MTHFD2 allosteric pocket.
  • Allosteric inhibition decreased the binding energy of an active-site inhibitor, confirming allosteric effects.

Conclusions:

  • The study identified promising natural product-like compounds for MTHFD2 inhibition.
  • These compounds show potential for developing new breast cancer therapeutics.
  • Targeting the MTHFD2 allosteric site is a viable strategy for drug development.

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