Development Of New Hemostatic Drugs Release Carrier For Minimally Invasive Surgery And Its Study Of Molecular Simulation

With the gradual development of quantum chemical methods,an increasing number of reports on the molecular weak interaction have emerged.These studies focus on static aggregates,such as benzene dimers,but seldom on dynamic changes,e.g.,an organic reaction.The deformation/interaction model is very suitable for studying the dynamic changes in the reaction process owing to it is easy to obtain the values of the interaction energy.In chapter 1,we used the semi-empirical method which named MP2 to investigate the interaction energy?E_i??activation energy?E_a?and deformation energy?E_d?changing of four classical bimolecular nucleophilic substitution reactions?S_N2?.The S_N2 reaction is appropriate for our study to achieve our objective,because inversion of the configuration?Walden inversion for a chiral molecule?occurs,the energy consumption is assumed to be large.The results of of energy analysis and conformational change indicate that the reaction of CH₃ Br + OH^-has the lowest E_a and E_d.For S_N2 reactions,the difficulty degree of a reaction reacting depends on the nucleophilicity of the nucleophile ion,we find that E_a and E_d similarly change with the order of nucleophilicity.More interestingly,E_i is a negative value at the TS,which is E_i positively contributes and “helps” the reaction cross the energy barrier.Weak interaction studies have shown that there are weak interactions in the four S_N2 reactions which can be "visualized" by using the contour surface.Meanwhile,we decompose E_i into four energies: the exchange,overlap and electrostatic energies decrease E_i,whereas the kinetic energy increases E_i.Analysis of the bond order,bond breaking?BB?and bond formation?BF?indices indicate that the TS of the reaction of CH₃ Br + OH^-appears earlier,that is,the reaction complex forms earlier which resulting a smaller E_a.At last,by analyzing the reaction rate constant and the tunneling factor,the reaction of CH₃ Br + OH^-has the highest reaction rate constant,that is,the reaction rate is the fastest which verified that the reaction of CH₃ Br + OH^-has the smallest E_a.Through these analyzes,we have a better understanding of the dynamic changes in the four reactions which can also provide clues to decrease the reaction barrier with the help of interaction energy.The mild postpartum hemorrhage,or long-term continuous abnormal uterine bleeding often induced by the exogenous injury and internal disease,such as coagulopathies or uterine atony,and so on.It would be a new tendency using MIS in controlling such an intracavitary hemorrhage.In chapter 2,we have established a method to use a multifunctional polymerizable sucrose monomer as a sustained release carrier to use in the MIS for hemostasis.This method solves the dilemma of flow and adhesion encountered in micro-channel transportation through photopolymerization.UV photolysis experiments show that the three amino acid structure of the photo-inert anti-fibrinolytic drugs and a quasi-light stabilized drugs can be used as carrier drugs.The photostability of the drug can also be illustrated by the recombination energy calculated by the excited state.The realtime infrared?RT-TR?experiments were used to obtain the polymerization kinetics of sucrose monomer,which indicates that the formula could be quickly photopolymerization and satisfied the requirements of rapid prototyping in clinical.Viscosity experiments show that the sucrose monomer has shear thinning characteristics which can be used by adding pressure to micro-channel transportation.Both sustained release experiments and hemostasis experiments in vitro confirmed that the cross-linked body formed by photopolymerization can not only as a drug carrier,but also allows the hemostatic drugs play the role of long-term sustained release hemostasis.At last,cytotoxicity experiments show that the cross-linked body has good bio-safety.In order to further study the mechanism of hemostasis,in chapter 3,we used molecular docking and molecular dynamics?MD?simulation to study the binding mechanism of four hemostatic drugs as ligands and human plasminogen kringle 1?1HPK?as the target.Through molecular docking,we can obtain the binding sites of the four drugs with 1HPK which shown that the hydrophobic interaction played an important role in the four docking complexes.The results of MD simulation calculations show that the complexes of diacetylaminoacetamide has the biggest fluctuation in the four docking complexes which is the most unstable.The results of binding free energy calculations show that the complex of aminomethyl benzoic acid has the strongest binding ability to 1HPK,while the complex of 6-aminocaproic acid is the weakest.Combining the results of sustained release experiments in vitro,tranexamic acid has a higher release amount and the complex has a larger binding free energy,so it is appropriate to take tranexamic acid as the minimally invasive hemostatic.