Phase Solubility Method Combined With Molecular Simulation To Study The Solubilization Mechanism Of Cyclodextrins On Six Natural Drugs

The special structure of cyclodextrin makes it possible to encapsulate the guest molecule to form a stable complex,thereby changing the physicochemical properties of the guest molecule.As an excellent inclusion material,cyclodextrin has important guiding significance for clinical use,pharmacokinetics and development of new drugs.In this paper,phase solubility,spectrometry,molecular docking simulations,and molecular dynamics simulations were used to investigate the flavonoids natural drugs fisetin and formononetin,alkaloids natural drugs camptothecin and vinpocetine,and coumarin natural drugs imperatorin and isoimperatorin.The mechanism of action of natural drugs and six cyclodextrins of BCD,DMBCD,2HPBCD,6Glu-BCD,ACD and GCD are as follows:The wavelength of absorption peak of flavonoid natural drugs fisetin wasλ=362 nm,formononetinλ=249 nm,alkaloids natural drug camptothecinλ=369 nm,vinorecetin absorptionλ=270 nm,The ubiquinone natural drugs imperatorinλ=303 nm,isoimperatorinλ=313 nm,the absorbance gradually increases with the increase of the cyclodextrin concentration,and the position of the maximum absorption wavelength does not change.There is a good linear relationship between the concentration of fisetin,formononetin,camptothecin,vinpocetine,imperatorin and imperatorin in a certain range and the absorbance,the solubility of fisetin pigment S₀=7.2×10^-6g/ml,formononetin S₀=1.09×10^-6g/ml,camptothecin S₀=3.4854×10^-6g/ml,Vinpocetine S₀=5.07×10^-66 g/ml,imperatorin S₀=6.15×10^-66 g/ml,isoimperatorin S₀=2.04×10^-66 g/ml.The phase solubility curves of the six drug system complexes are A_L type,inclusion constants fisetin K_{DMBCD-fisetin}>K_{2HPBCD-fisetin}>K6Glu-BCD-fisetin)>KGCD-fisetin)>K_BCD-fisetin>K_ACD-fisetin,formononetin K_{6Glu-BCD-form}>K_DMBCD-form>K_2HPBCD-form>K_BCD-form>K_GCD-form>K_ACD-form,Camptothecin K_DMBCD-cam>K_2HPBCD-cam>K_BCD-cam>K_6Glu-BCD-cam>K_ACD-cam>K_GCD-cam,Vinpocetine K_BCD-vin>K_GCD-vin>K_2HBPCD-vin>K_DMBCD-vin>KACD-vin)>K_6Glu-BCD-vin,Imperatorin K_DMBCD-imp>K_2HPBCD-imp>K_BCD-imp>K_6Glu-BCD-imp>K_GCD-imp>K_ACD-imp,isoimperatorin K_{2HPBCD-isoimp}>K_DMBCD-isoimp>K_BCD-isoimp>K_{6Glu-BCD-isoimp}>K_GCD-isoimp>K_ACD-isoimp.The six drug guest molecules can be well encapsulated by the cyclodextrin host,and the host-guest clathrate can better increase the water solubility and thermal stability.It was hypothesized that fisetin,formononetin camptothecin,vinpocetine,imperatorin,and isoimperatorin could form a 1:1 complex with cyclodextrin,respectively.The change in the peak intensity of the physical mixture and the complex in the infrared spectroscopy demonstrated that the six natural drug objects were encapsulated in the host cyclodextrin to form a complex.Molecular docking simulation method was used to obtain the stable complex structure that the drug and cyclodextrin may form.The force of interaction is hydrogen bond and hydrophobic.Quantum chemical energy calculates the lowest energy data△E<0.It is concluded that these six natural drugs form a complex with cyclodextrin,and the binding modes in the above docking simulation are consistent.Molecular dynamics shows that there has not been much change by observing changes in atomic displacements,changes in the positions of ligand atoms,changes in the total number of specific contact points,and changes in surface area,solvent accessible surface area,and polar surface area.The set-up of the cyclodextrin and drug has the same structural pattern,and it is speculated that six natural drugs can form a 1:1 stable complex with cyclodextrin.The verification experiment of infrared spectroscopy combined with molecular docking simulation and molecular dynamics simulation is basically the same as the structure obtained from the phase solubility experiment.It can be said that flavonoids fisetin and formononetin,alkaloids camptothecin and vinpocetine and coumarins imperatorin and isoimperatorin can indeed form a 1:1 stable complex with cyclodextrin.