[Retracted] In silico study on inclusion complex of sorafenib and regorafenib with modified cyclodextrins

Aamir Aman, Graduate School

Abstract

Sorafenib (SOR) and regorafenib (RG) are oral multikinase inhibitors that effectively hamper the growth and spread of cancer cells by targeting angiogenesis and proliferation. However, both of the drugs have low water solubility. To address this issue, cyclodextrins (CDs), widely used to enhance the solubility and stability of lipophilic drugs by encapsulating them within their molecular structure, were considered in this study. We focused on β-cyclodextrin (βCD) and its derivatives, including hydroxypropyl-β-cyclodextrin (HPβCD), dimethyl-β-cyclodextrin (DMβCD), sulfobutylether-β-cyclodextrin (SBEβCD), and compared them with γ-cyclodextrin (γCD) for generating inclusion complexes with SOR and RG. The 200-ns molecular dynamics simulations revealed that both drugs could form inclusion complexes with all CDs in two possible orientations: pyridine group insertion (P-form) and chlorobenzotrifluoride group insertion (C-form), primarily driven by van der Waals interactions. Among the four βCD derivatives studied, SOR and RG exhibited the highest number of atom contacts with SBEβCD and demonstrated the lowest solvent accessibility within the hydrophobic cavity. These findings correlated with the highest binding affinity determined by SIE, MM/GBSA, and MM/PBSA methods. Experimental results further supported our computational predictions, as SOR/SBEβCD exhibited a stability constant of 940 M-1 while the Kc value of RG/SBEβCD was 640 M-1 at 25 °C, surpassing βCD's stability constant of 210 M-1 and 240 M-1 respectively. Taken together, our results suggest that modified CDs, particularly SBEβCD, hold promising potential as an efficient molecular encapsulating agent for both SOR and RG, offering improved solubility and stability for these lipophilic drugs. While trying to analyze βCD with different methyl substitutions it was observed that 13-MβCD exhibits a distinct conformation characterized by a predominantly circular shape, low likelihood of flipping, and cavity enclosure and could be considered a more suitable host for encapsulating low-water soluble compounds.