A detailed computational study on binding of kinase inhibitors into β-cyclodextrin: inclusion complex formation

It is well known that the limited aqueous solubility of some drugs often reduces their bioavailability to targets. Inclusion complex formation of drugs with beta-cyclodextrin is one of the best approaches for drug delivery improvement. Extensive microscopic molecular dynamics simulations were performed to study the interactions between beta-cyclodextrin and a class of kinase inhibitor drugs. Solvation free energy calculations demonstrated that these drugs are insoluble in water and reinforced the need for a carrier to increase the solubility. The binding of these drugs into beta-cyclodextrin was assessed by calculating the binding free energy, and it was found that all drugs tended to be bound thermodynamically. Examination of the dynamic properties showed that the drugs were loaded into beta-cyclodextrin, so due to the loading of drugs into the beta-cyclodextrin, the mean square displacement (MSD) of all the drugs drastically decreased. The loading of drugs was accompanied by pushing of water out of the center of the beta-cyclodextrin cavity. The drugs showed different orientations and mechanisms for loading into beta-cyclodextrin. By studying the root mean square fluctuation (RMSF), it was revealed that the drugs were flexible in interaction with beta-cyclodextrin; in contrast, beta-cyclodextrin retained its rigidity in all simulated systems.

Automated summary

The limited aqueous solubility of certain drugs can reduce their bioavailability, making inclusion complex formation with beta-cyclodextrin a promising method for drug delivery enhancement. Extensive molecular dynamics simulations revealed that these drugs are insoluble in water and require a carrier to increase solubility. The binding of these drugs into beta-cyclodextrin was thermodynamically favorable, leading to improved solubility and bioavailability.