In silico drug screen reveals potential competitive MTHFR inhibitors for clinical repurposing

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Keske N., Ozay B., Tukel E. Y., Mentes M., Yandim C.

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, vol.41, no.21, pp.11818-11831, 2023 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 41 Issue: 21
  • Publication Date: 2023
  • Doi Number: 10.1080/07391102.2022.2163697
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE
  • Page Numbers: pp.11818-11831
  • Keywords: cancer, Docking, drug screen, inhibitor, molecular dynamics, MTHFR, PyRx, repurposing
  • Dokuz Eylül University Affiliated: No


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 (beta 2-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