| Molecular dynamics simulation is an important research method to study the structure and properties of molecules or molecular systems through computer simulation.It has become a new research method in the fields of biology,chemistry,pharmaceutical preparations and so on.Among them,the coarse-grained molecular dynamics simulation simplifies the molecular structure and greatly improves the computational efficiency,which can study biomolecular processes at a larger scale.The molecular structure of traditional Chinese medicine(TCM)is complex,and some of them have special properties such as self-assembly and phase transition.The study of TCM involves a large number of interactions between drugs and drugs,drugs and excipients,and even with biological organisms,such as drug loading and release,drug permeation through membrane,etc.Limited by classical experiments,it is difficult to deeply explain the internal mechanism at the molecular scale.Coarse-grained simulation provides a new research idea for the study of TCM molecules and their related research in the field of TCM preparations.In the study of coarse-grained molecular dynamics simulation,a reasonable and reliable coarse-grained force field is the prerequisite to ensure the accuracy of the simulation results.However,since coarse-grained simulation is still mostly used for the simulation of large molecules such as proteins and polymers,there is a lack of methods for constructing coarse-grained force fields for small molecules.As a result,the coarse-graining force field of TCM molecules is lacking,which greatly limits the application of coarse-graining simulation methods in the field of TCM research,and also leads to the lack of methodological guidance of coarse-graining simulation in TCM research.Therefore,in order to improve the coarse graining force field parameters of chemical components of TCM and provide guidance for coarse graining simulation in the study of TCM,this paper mainly carried out the following three aspects:(1)Construction and verification of force field of small molecules of TCMIn this part,based on the parent core structures of four typical TCM types,including phenylpropanoids,quinones,flavonoids and terpenoids,24 small molecules of TCM were screened to construct the coarse-grained structure.According to the results of all-atom simulation,the coarse-grained force field parameters were obtained by combining with relevant kinetic simulation software to construct the coarse-grained force field.Bond length,bond Angle,dihedral Angle,solvent accessible surface area and radius of gyration were used as evaluation parameters to evaluate the rationality of the force field structure.The solvation free energy was used to evaluate the parameters to evaluate the rationality of the thermodynamic properties of the coarse-grained force field.The results showed that the constructed force field had good structure and thermodynamic properties,which could directly provide force field parameters for the coarse rained molecular dynamics simulation of TCM small molecules,and lay the foundation for the subsequent development of force field database of Chinese medicine small molecules.In addition,based on the process of force field development,the principle of coarsegrained force field construction for TCM small molecules is proposed,which provides a reference for the development of coarse-grained force fields for other TCM small molecules.(2)The simulation study of β-cyclodextrin inclusion of TCM small moleculesIn this part,solubilization,an important link in TCM preparation,was used as an application scenario to verify the rationality of the established force field for the coarse granulation of TCM small molecules in practical application.Ferulic acid(FER)(a monocyclic phenylpropanoid)and osthole(OST)(a bicyclic phenylpropanoid),which are commonly used for the inclusion of β-cyclodextrin(β-CD)to improve its solubility,were selected.The coarsegrain simulation method was used to simulate the inclusion process of β-CD.At the same time,the saturated aqueous solution method,which is most commonly used in macroscopic experiments,was used to prepare β-CD inclusion complexes.The inclusion effects of β-CD on the two drugs were compared at the simulation and macroscopic experimental levels,and the mechanism of different inclusion effects of β-CD on different drugs was studied at the molecular scale by means of coarse-grained simulation.The results showed that the trend of the inclusion effect of the two drugs was consistent in the simulation and classical experiments.When the drug was smaller,rod-shaped and had strong interaction with β-CD,it was more likely to form inclusion complexes with β-CD.The above results show that the constructed coarse-grained force field can reproduce the experimental results,which verifies the rationality and accuracy of the constructed force field in practical application scenarios.At the same time,the mechanism of β-CD inclusion drugs was explored to provide theoretical guidance for the application of β-CD in drug preparation development.On this basis,the inclusion rate was introduced as the simulation evaluation parameter in combination with classical experiments,which further improved the evaluation parameter system of coarse-grained simulation in β-CD inclusion research,strengthened the correlation between simulation and macroscopic results,and provided methodological guidance for related applications.(3)The simulation study of transdermal penetration of small molecules of TCMIn this part,the percutaneous penetration of drugs was used as an application scenario to verify the rationality of the established force field of small molecules of TCM in practical application.Three kinds of permeabilizing agents(cinene,cineole,terpineol)were used to promote the transdermal permeation of lipophilic drug OST.The distribution of drugs in the lipid membrane before and after the addition of different permeabilizing agents was investigated,and the permeation ability and effect of different permeabilizing agents were compared.The results showed that the distribution of OST in the lipid membrane was increased by cinene>cineole≈terpineol.At the same time,the effects of three permeabilizers on lipid membrane and OST were studied at the molecular scale to further explore the mechanism of permeabilizing agents and provide guidance for further research and application of permeabilizing agents.The results showed that the permeability enhancers could play a role by reducing the degree of lipid arrangement,improving lipid fluidity,accelerating drug diffusion,and enhancing the interaction between OST and lipid membrane.The above results show that the simulation results can reproduce the results of classical experiments,indicating that the constructed force field is reasonable and reliable.At the same time,the discussion of the mechanism of three kinds of permeabilizing agents provides data support for the related research of transcutaneous penetration of chemical components of TCM.On this basis,combined with the classical experiment,permeability was introduced as the simulation evaluation parameter,which further improved the evaluation parameter system of coarsegrained simulation in drug permeation through membrane,and provided method guidance for related applications.In summary,we constructed a series of coarse-grained force fields of TCM small molecules and developed a set of coarse-grained force field parameterization methods suitable for TCM small molecules.On this basis,the coarse-grained force field of some small molecules of TCM was selected to study the effect and mechanism against the background of the actual application scenario of TCM pharmaceutics,which further verified the rationality of the coarsegrained force field constructed in this paper.At the same time,the evaluation system of simulation method was improved to provide method reference for the application of coarsegrained simulation in TCM research. |
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