Research On Prediction Method Of Intestinal Absorption Of Chinese Medicine Components Based On QSPR And Molecular Dynamics Simulation

Oral administration is the most common clinical administration route for traditional Chinese medicine preparations because it is relatively safe and easy to be accepted by patients.The small intestine is the main place for drug absorption and the main barrier for drug absorption.After oral administration,most drugs need to pass through the cell membrane of small intestinal cells through passive diffusion or carrier-mediated active transport to reach the whole body blood circulation.In the early stages of new drug development.evaluating the intestinal absorption of drugs can improve the success rate of rearch and development.At present,the evaluation of drug intestinal absorption performance mainly includes animal and cell models.However,the complexity of drug absorption and the limitations of conventional models have affected the development of new drugs.In response to the above problems,this paper introduces mathematical models and computer simulation studies into the study of drug intestinal absorption prediction,complements each other with conventional experimental models,and aims to establish a simple and efficient intestinal absorption prediction model of traditional Chinese medicine ingredients,which provides more Multiple method support.To this end,this article mainly carried out the following aspects of work1.QSPR Study on Intestinal Absorption Performance of Traditional Chinese MedicineIn this section,Quantitative structure property relationship(QSPR)is applied to the establishment of a drug absorption prediction model.For 48 Chinese medicine components,12 structure descriptors that have a great influence on the absorption rate are selected.Optimal MLR and PLS models were constructed,and model's estimation ability,stability and predictive ability were verified,and each compound was divided by cluster analysis based on QSPR descriptors.The results showed that the optimal models established in this paper meet the relevant standards such as Golbrailch-Tropsha,and both models had good predictive ability for the selected drugs and external test sets,but in practical application,PLS is better than MLR model.The results of the descriptors showed that the thermodynamic descriptors(including heat of formation and ALogP98),the structural descriptors(including the number of hydrogen bond donors and rotatable bonds),and the spatial stereoscopic descriptors(including Ellipsoidal volume,Principal moment of inertia Z and Radius of gyration,etc.)had a more important effect on the absorption rate.Cluster analysis showed that a class of compounds with a higher absorption rate was closely related to the size of seven descriptors,three of which were key parameters that affect the absorption rate of drugs.The QSPR model established in this paper has good performance and can easily and directly predict the absorption of drugs.Each compound can be clustered according to key descriptors.This method is relatively simple,green and economical,and has certain practical significance and feasibility for general use in drug research and development.2.Study on Mechanism of Drug Permeable Absorption Based on Small Intestine Epithelial Cell Membrane ModelIn this section,molecular dynamics simulations were applied to the construction of small intestinal epithelial cell membranes and the evaluation of drug permeable membrane absorption prediction.A small intestinal epithelial cell membrane system close to the true ratio was constructed,and the effect of temperature and moisture changes on the membrane properties was investigated.The processes of free diffusion of drugs into and dragging through the membrane of different models were simulated respectively,and the free diffusion rate and the ability of the membrane to penetrate the membrane were characterized by the parameters such as the change in free energy of the drug molecule during the membrane penetration.The results showed that the membranes at physiological temperature were in good condition,which was conducive to the subsequent study of drug transmembrane absorption;free diffusion characterization of model drugs was same as the tendency of the drug permeability of each model reflected by the free energy barrier of the transmembrane,and can jointly characterize the absorption rate of the drug;the size of the drug permeable energy barrier has a good correlation with the prediction result of the QSPR model.The smaller the membrane barrier in a pure lipid membrane,the better the drug permeability.Correlation analysis of the parameters that characterize the absorption rate in different models showed that the Caco-2 single-layer model.QSPR model and molecular dynamics model had good predictive ability in drug absorption.The transmembrane absorption process of drugs between each model can complement and verify each other,and jointly provide a basis for drug absorption prediction.3.Study on the interaction between drugs and P-gp In this section,the interaction between drugs and P-glycolprotein(P-gp)is studied in response to the problem that some drugs may be affected by the efflux of P-gp and restrict their intestinal absorption.P-gp was embedded in the lipid membrane system,and the stability of the system after protein embedding was evaluated;the distance between the drug and the protein was characterized to observe the drug's movement trend in the protein pore cavity;in order to further analyze the efflux effect of proteins on drugs,we compared the changes of the free energy potential energy surface of P-gp when P-gp was embedded in the phospholipid bilayer membrane and the cytoplasmic solution.The results showed that:after embedding the protein,the arrangement of lipid molecules was disturbed to a certain extent;some drugs had a more obvious effect on the protein structure and the structural changes of specific lipid molecules.Preliminary judgments were related to their use as substrates.The change in the distance between residues and drugs also confirms this.Through the change trend of free energy potential energy surface,the difference of each drug was analyzed.This part of the study provided a reference for the identification of P-gp substrates and drug-protein interaction studies.In summary,this article applies QSPR and molecular dynamics simulation to intestinal absorption research of Chinese traditional medicine ingredients,constructs QSPR absorption rate prediction model.characterizes relevant parameters of absorption rate from the simulation level,and expands the research methods of intestinal absorption of Chinese traditional medicine ingredients,which provides new ideas for the in vitro prediction of intestinal absorption of oral drugs.