Radicicol as a Dual-Site Inhibitor of Isoprenylcysteine Carboxyl Methyltransferase: A Computational Study.

Background: Isoprenylcysteine carboxyl methyltransferase (ICMT) is an enzyme crucial for the post-translational processing of Ras oncoproteins. Pharmacological inhibition of ICMT can mislocalize Ras and disrupt oncogenic signaling, exhibiting anticancer effects. Radicicol (RAD) is a 14-membered resorcylic acid lactone biosynthesized by fungi and possesses diverse bioactivities. Objective: The current work explored RAD's interaction with ICMT through molecular docking and molecular dynamics simulations, comparing Radicicol's binding mode to that of the native ICMT ligand. Method: Docking simulations were performed using Glide XP mode, and binding energies were refined by MM-GBSA calculations. Molecular dynamics simulation of 100 ns was conducted to assess the binding stability of the Radicicol-ICMT complex using Desmond, with analysis of RMSD and protein-ligand interactions. Results: Molecular docking and molecular dynamics simulations revealed that RAD stably bound within the ICMT active site by bridging both the S-adenosylmethionine cofactor pocket and the hydrophobic prenyl substrate tunnel. Its key interactions included a persistent hydrogen bond with Val116 and an induced-fit engagement of Arg125, supporting a snug and stable RAD-ICMT complex. Conclusion: These computational insights suggested that RAD inhibited ICMT by dual-site binding, simultaneously occupying the cofactor and substrate pockets. Such a dual engagement could mislocalize prenylated proteins (like Ras) and represent a novel mechanism of action for RAD.