Exploring the Interactions of Ferrocenylmethylnucleobase Derivatives With BSA and HHb: Insights From Electrochemical, Spectroscopic, ADMET, in Silico Docking, and MD Simulations

Abstract The present study has investigated the binding interactions of four N‐ferrocenylmethyl‐nucleobase derivatives: N1‐ferrocenylmethyladenine (FcMeAd), N1‐ferrocenylmethyl‐cytosine (FcMeCy), N1‐ferrocenylmethylthymine (FcMeTh), and N6,9‐bis(ferrocenyl‐methyl)adenine ((FcMe) 2 Ad), with human hemoglobin (HHb) and bovine serum albumin (BSA). A combination of absorption spectroscopy, cyclic voltammetry, molecular docking, and molecular dynamics simulations is employed to investigate these interactions. The obtained results demonstrated that these derivatives can bind to the target proteins, inducing conformational changes with the binding affinity order: FcMeCy > FcMeTh > FcMeAd > (FcMe) 2 Ad. Molecular docking studies identified the preferred binding sites and modes, revealing that hydrogen and hydrophobic predominantly facilitate the binding to BSA and HHb, also exhibiting π–π stacking interactions with FcMeCy and FcMeAd. Dynamic simulations of the FcMeCy‐BSA and FcMeCy‐HHb complexes, selected based on both experimental and theoretical results, further confirmed their stability within the protein binding pockets. The RMSD, RMSF, rGyr, SASA, H‐bonds, MolSA, and PSA parameters consistently indicated that FcMeCy maintains stability in the receptor binding site throughout the 100 ns simulation.