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Updated: Aug 15, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
In silico drug screen reveals potential competitive MTHFR inhibitors for clinical repurposing
Nazlıgül Keske1, Başak Özay1, Ezgi Yağmur Tükel1
1Faculty of Engineering, Department of Genetics and Bioengineering, İzmir University of Economics, Balçova, İzmir, Turkey.
Abstract:
MTHFR (Methylenetetrahydrofolate reductase) is a pivotal enzyme involved in one-carbon metabolism, which is critical for the proliferation of cancer cells. In line with this, published literature showed that MTHFR knockdown caused impaired growth of multiple types of cancer cells. Moreover, higher MTHFR expression levels were linked to shorter overall survival in hepatocellular carcinoma, adrenocortical carcinoma, and low-grade glioma, bringing the need to design MTHFR inhibitors as a possible treatment option. No competitive inhibitors of MTHFR have been reported as of today. This study aimed to identify potential competitive MTHFR inhibitor candidates using an in silico drug screen. A total of 30470 molecules containing biogenic compounds, FDA-approved drugs, and those in clinical trials were screened against the catalytic pocket of MTHFR in the presence and absence of cofactors. Binding energy and ADMET analysis revealed that Vilanterol (β2-adrenergic agonist), Selexipag (prostacyclin receptor agonist), and Ramipril Diketopiperazine (ACE inhibitor) are potential competitive inhibitors of MTHFR. Molecular dynamics analyses and MM-PBSA calculations with these compounds particularly revealed the amino acids between 285-290 for ligand binding and highlighted Vilanterol as the strongest candidate for MTHFR inhibition. Our results could guide the development of novel MTHFR inhibitor compounds, which could be inspired by the drugs brought into the spotlight here. More importantly, these potential candidates could be quhickly tested as a repurposing strategy in pre-clinical and clinical studies of the cancers mentioned above.Communicated by Ramaswamy H. Sarma.
Insights
Methylenetetrahydrofolate reductase (MTHFR) is crucial for cancer cell growth. This study identified Vilanterol, Selexipag, and Ramipril Diketopiperazine as potential MTHFR inhibitors through in silico screening, offering new cancer treatment strategies.
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- Methylenetetrahydrofolate reductase (MTHFR) is vital for one-carbon metabolism and cancer cell proliferation.
- Elevated MTHFR expression correlates with poorer survival in several cancers, necessitating targeted inhibitors.
- Currently, no competitive MTHFR inhibitors are available.
Purpose of the Study:
- To identify potential competitive MTHFR inhibitors using computational drug screening.
- To evaluate identified compounds for their binding affinity and drug-like properties.
- To explore novel therapeutic strategies for MTHFR-dependent cancers.
Main Methods:
- Performed an in silico drug screen of 30,470 molecules against the MTHFR catalytic pocket.
- Assessed binding energy and ADMET properties of potential inhibitors.
- Utilized molecular dynamics and MM-PBSA calculations to analyze ligand-protein interactions.
Main Results:
- Identified Vilanterol, Selexipag, and Ramipril Diketopiperazine as potential competitive MTHFR inhibitors.
- Vilanterol demonstrated the strongest binding affinity for MTHFR.
- Key amino acid residues (285-290) were identified as crucial for ligand binding.
Conclusions:
- Vilanterol, Selexipag, and Ramipril Diketopiperazine are promising candidates for MTHFR inhibition.
- These compounds could serve as a basis for developing novel MTHFR-targeted cancer therapies.
- Drug repurposing of these candidates warrants investigation in preclinical and clinical cancer studies.
