Preparation And Evaluation Of Cinnamaldehyde Ethosomes Gel Based On Molecular Docking

Objective:With the prolongation of life expectancy,the improvement of living standards,the increase of consumption of sugary drinks,and the rapid decline of physical activity,the prevalence of diabetes will become higher and higher,and the harmfulness of diabetes complicated with cardiomyopathy will become increasingly prominent.In this context,we intend to screen out the active monomers against methylglyoxal?MG?from the many chemical constituents of the national drug cinnamon,conduct appropriate formulation research,and explore its mechanism of action on Diabetic Cardiomyopathy?DCM?,and provide reference for the prevention and treatment of DCM.Methods:The mature and advanced"Computer-Aided Drug Design"?CADD?technology was used to screen the appropriate lead compounds by database screening and molecular docking techniques.The molecular docking process of the lead compounds was verified by molecular dynamics simulation.The lead compound was finally selected as cinnamaldehyde.Literature analysis was used to comprehensively study the relationship between cinnamaldehyde,diabetes,DCM,Transient Receptor Potential Ion Channel 1?TRPA1?,and MG.The content determination method of cinnamaldehyde was determined by high performance liquid chromatography?HPLC?,and the pH stability of cinnamaldehyde was studied.The preparation of cinnamaldehyde ethosomes?CA-ES?was optimized by single factor and orthogonal test,and its particle size,potential,appearance,morphology was evaluated by formulation.Optimize the screening process of cinnamaldehyde ethosomes gels?CA-ES-gels?by controlled variable method,prepare three batches of preparations by optimal preparation process,conduct quality evaluation and content determination method research,and carry out mice in vitro and in vivo transdermal absorption studies.A mice model of DCM was established by"high-sugar and high-fat diet feeding"combined with"peritoneal injection of alloxan"method,and the model was evaluated by pathological sectioning HE staining method.In addition,the glibenquinone ethosomes gels was used as the positive drug,and the anti-DCM effect of CA-ES-gels was explored with double blank control.MG and cardiac troponin I?cTnI?in mice was detected by ELISA at16th and 20th week of modeling,statistical analysis of data through SPSS.RESULTS:A total of 12 lead compounds were obtained from the initial screening of the database.The molecular energy of the molecular docking was best with trans-cinnamaldehyde.The real-time trajectory and interaction diagram obtained by molecular dynamics experiments showed that cinnamaldehyde could competitively inhibit the binding of MG to TRPA1.The results of literature analysis showed that Ca²⁺influx in cardiomyocytes is the most important cause of cardiomyopathy;TRPA1 is the main receptor mediating cellular Ca²⁺influx;MG can mediate Ca²⁺influx by activating the TRPA1receptor on the cell surface,leading to myocardial lesions;cinnamaldehyde can inhibit cardiomyocyte Ca²⁺influx by activating TRPAl.The optimum preparation conditions for CA-ES are:water bath temperature is 35?,ethanol dosage is 40%,lecithin dosage is 4%,and cinnamaldehyde dosage is 2%.The average encapsulation efficiency of the three batches of CA-ES prepared was 76.61%,and its morphology was a globular structure with an average particle size of 201.2 nm,a PDI of0.24,and a ZETA potential of-2.191 mV.The optimum preparation conditions for CA-ES-gels are:carbomer mass concentration0.5%,solvent 40%ethanol solution,CA-ES to carbomer matrix ratio of 1:3,and triethanolamine pH adjustment of 6.7.The three batches of CA-ES-gels prepared were white translucent with an average pH of 6.63 and an average content of 6.71 mg/g.The in vitro and in vivo transdermal absorption tests showed that CA-ES-gels had good skin permeability and safety,the transdermal absorption curve is linear,indicating that CA-ES-gels still have a sustained release effect.The blood glucose changes,behavioral manifestations and pathological sections of the mice showed that the mice DCM model was successfully prepared.Animal experiments showed that the preparation of CA-ES-gels by cinnamaldehyde significantly improved the drug efficacy and decreased the blood glucose,serum MG and cTnI of the mice DCM model?p<0.05?.And the CA-ES-gels also delayed the"secondary injury"caused by high glucose environment in mice,successfully reduced the mortality of DCM mice and prolonged the survival time of DCM mice.Conclusion:Through the"structure-based drug design"technology,the active lead compound was successfully selected from the many compounds of cinnamon as cinnamaldehyde,and it was successfully made into cinnamaldehyde plastid gel.Comprehensive analysis of the results of literature analysis,molecular docking,molecular dynamics simulation tests and preliminary pharmacodynamic tests,we believe that cinnamaldehyde has the effect of preventing and treating diabetic cardiomyopathy,and its mechanism may be through competitive inhibition of the binding of methylglyoxal to TRPA1.Prevent Ca²⁺from entering the cardiomyocytes,reduce the oxidative damage of cardiomyocytes,and thus achieve the purpose of preventing and treating diabetic cardiomyopathy.In this paper,through the"computer-aided drug design"technology,the active lead compound was successfully selected from many cinnamon compounds to be cinnamaldehyde,and it was successfully made into CA-ES-gels.Based on a comprehensive analysis of the results of literature analysis,molecular docking,molecular dynamics simulation tests and preliminary pharmacodynamic tests,we believe that CA-ES-gels have the effect of preventing and treating DCM,and its mechanism of action may be through competitively inhibit the binding of MG to TRPA1.So that the flux of Ca²⁺into cardiac myocytes was reduced,thus the synthesis,cross-linking and deposition of collagen were reduced to achieve the purpose of preventing and treating DCM and improving the survival rate of DCM mice.