Molecular mechanism for the encapsulation of the doxorubicin in the cucurbit[n]urils cavity and the effects of diameter, protonation on loading and releasing of the anticancer drug:Mixed quantum mechanical/ molecular dynamics simulations

Background and objectives: Doxorubicin is a common apoptotic chemotherapeutic which has shown an obvious inhibitory effect in cancer chemotherapy. Here, cucurbit[n]urils (n = 7,10) have been proposed as a doxorubicin carrier, and the effects of diameter, protonation on loading and releasing of the anticancer drug doxorubicin has been studied.

Methods: The Density Functional Theory (DFT) calculation and Molecular Dynamics (MD) simulation are performed to study the adsorption process of the (guest) Doxorubicin molecule in the neutral and protonated states within the (host) cucurbit[n]urils (n = 7,10).

Results: DFT results show that the adsorption process in water is thermodynamically favorable. It is found that the binding energies for protonated drug encapsulation in cucurbit[n]urils are weaker than those of the neutral drug, implying the protonation of doxorubicin can promote the drug release from the adsorption situation. The electron density values and their Laplacian are evaluated to identify the nature of the intermolecular interactions through the topological parameters using the Bader's theory of atoms in molecules. Furthermore, the natural bond orbital analysis shows that the electrons aretransferred from cucurbit[n]urils to drug in all complexes. MD simulation results indicate that value of drug diffusion coefficient is small, therefore, we expect DOX to be slowly released from the CB cavity.

Conclusions: Based on obtained results, cucurbit[n]urils may be a prominent nano-carrier to loading and release drug on to target cells.

Keywords: Cucurbit[n]urils; Density functional theory; Doxorubicin; MM-PBSA; Molecular dynamics simulation.