Effects of F53 hotspot mutations on the molecular dynamics of MEK1 protein and the binding of its FDA-approved inhibitors

Vural B. E., Yandım C.

International Journal of Biological Macromolecules, cilt.306, 2025 (SCI-Expanded, Scopus)

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 306
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.ijbiomac.2025.141329
  • Dergi Adı: International Journal of Biological Macromolecules
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, Food Science & Technology Abstracts, INSPEC, Veterinary Science Database
  • Anahtar Kelimeler: MEK1, F53, Inhibitor
  • Dokuz Eylül Üniversitesi Adresli: Hayır

Özet

MEK1 (MAP2K1) could emerge as an oncogenic protein in the presence of certain mutations, and could be inhibited by FDA-approved drugs (trametinib, cobimetinib, binimetinib and selumetinib). However, how the mutations on MEK1's hotspot residue F53 affect the bindings of these therapeutic molecules remained largely unexplored. We performed molecular dynamics (MD) simulations with wild-type and mutated (F53L/V/C/I/Y) MEK1 structures in the presence and absence of these drugs and observed changes on the motion of MEK1. A longer duration in the lowest energy state conformation was observed during the simulations in the presence of F53 mutations. This was complemented by cross-correlated motions of amino acids of MEK1. More importantly, the binding affinities of inhibitors were affected. There was a marked reduction in the calculated binding affinity of trametinib in the presence of F53C mutation. On the other hand, the binding affinities of cobimetinib and selumetinib could overcome F53 mutations on MEK1. Binimetinib interestingly exhibited an increased binding affinity when F53C/I mutations were present. Taken together, our results provide a comprehensive perspective on the structural and drug-binding effects of observed mutations on the hotspot residue F53 within MEK1; warranting further research in stratifying F53 hotspot mutations for effective drug binding.