Epichlorohydrin-crosslinked β-cyclodextrin polymers (pCDs) are versatile drug carriers that solubilize poorly water-soluble molecules and exhibit intrinsic biological activity. However, the broad dispersity and ill-defined architecture of conventionally synthesized pCDs have hindered structure–property correlations at the molecular level. In this work, the synthesis of pCDs with well-defined molecular weights and low dispersities, is reported. The three fractions are fully characterized for composition, size, and supramolecular organization. All pCD fractions enabled substantially higher linezolid (LZD) solubilization than native βCD, with stability constants independent of molecular weight. NMR spectroscopy revealed a tilted aromatic insertion geometry for LZD within the βCD cavity and identified additional drug interactions in inter-cavity microdomains unique to the polymer. An atomistic pCD model, constructed for the first time, was subjected to molecular docking and microsecond molecular dynamics simulations. LZD preferentially associated with inter-cavity regions rather than undergoing spontaneous cavity inclusion, with binding limited primarily by kinetic and steric constraints rather than geometric incompatibility. These findings establish that pCDs bind drugs through multiple complementary modes and demonstrate experimentally grounded atomistic simulation as a powerful framework for rational design of carbohydrate-based drug delivery platforms.
Jesus Alfredo Godinez-Leon, Tahmida Shamsuddin, Maria Fontenele, Vincent Dumouilla, Baptiste Boit, Mathilde Audrey Pondy Bias, Jean-Pierre Baltaze, Amandine Dos Santos, Mohamed Haouas, Luc Picton, Christophe Rihouey, Claude-Gilles Dussap, Ruxandra Gref (2026) Cyclodextrin polymers efficiently incorporate linezolid through multiple binding modes: insights from experiments and molecular simulations. Carbohydrate Polymers 393, 125978.
https://doi.org/10.1016/j.carbpol.2026.125978.