Study On The Structure,Properties And Docking Mechanism Of Anti-cancer Drug Docetaxel

Objectives:Taxol(paclitaxel)is an anti-cancer drug with strong anti-cancer activity,after a long research by scholars,the mechanism,activity,and drug targets have made good progress.Therefore,Taxol is widely used in current cancer treatments.However,Taxol also has the problems of low water solubility,large toxic,side effects,and strong patient dependence.Taxotere(Docetaxel)also known as docetaxel,is an analogue of paclitaxel.Docetaxel has only two differences with paclitaxel in structure.Taxol compared to paclitaxel with low toxicity side effect and excellent water solubility.Therefore,the reasearch on the mechanism,activity,target of docetaxel has become a hot spot.In this article,by the optimization of the structure of docetaxel,discussion of related properties,analysis of the mechanism of docetaxel and tubulin,microscopic dynamic processes of docetaxel and tubulin by molecular dynamics simulation.The detailed structural parameters,physicochemical properties and active sites of docetaxel were obtained.A comprehensive study of docetaxel drug molecules which can provide relatively complete and detailed data for other docetaxel drug research scholars and provide a powerful reference,and help save exploration time and save experimental costs.Methods:Our team initially obtained 3888 docetaxel structures through the rotation of the C-13 side chain.The resulting structure was optimized by the PM7 method of the MOPAC software and get 648 structures.Using Gaussian 09 to optimize the structure,a total of 31 docetaxel structures were obtained after optimization using B3LYP/3–21G* method and B3LYP/6–311G* method.Relative energies are reported at the M06-L/6–311G(2df,p)//B3LYP/6–311G* level.Solvated energy and single point energy are calculated using the M06L/6-311G(2df,p)//B3LYP/6-311G* method.The excited electronic states of the docetaxel were studied using the TDDFT/CAM-B3LYP/6-31+G(d)method;After obtaining the experimental simulation structure,our team used the Autodock 4.2(molecular docking software)for molecular docking of 31 structures,tubulin is 1tub.A grid of 126,126,and 126 points in x,y,and z directions was created for the entire global docking and A grid of 60,60,and 60 points in x,y,and z directions was created for the entire local docking,and generate 100 docking results.Through the docking results to find their drug targets and statistical analysis showed many structures with better binding effect;Molecular dynamics simulations were performed for the lowest binding energy conformations between docetaxel and b-tubulin using the Gromacs 5.0 software with the Gromos96(43A1)force field.The topology file of docetaxel was obtained from PRODRG 2.5.After energy minimization,each DTX was equilibrated with position restraint on b-tubulin for 1000 ps using the NVT and NPT ensembles to get more reliable results,production MD was performed for 10 ns time durations.Results:We obtained 31 globally most stable structures with the lowest energy on the potential energy surface in 3888 kinds of tentative structures by ab initio method.We were obtained the single point energy,relative energy,solvation energy,zero vibrational energy,rotation constant,dipole moment and other parameters of 31 kinds of structures.The infrared vibrational spectra and ultraviolet absorption spectra of the lowest 31 taxanes were analyzed.docetaxel molecule-related valence orbits are mainly excited by ?,n,and ? orbits.In the literature,HOMO,HOMO-3,HOMO-6,and HOMO-7 molecules all belong to ?-orbital excitation.The excitation of n and ? orbits is mainly concentrated on oxygen and nitrogen atoms.HOMO,HOMO-3,HOMO-4,HOMO-5,HOMO-7,HOMO-12 all belong to n or ? orbital excitation,LUMO,LUMO+1,LUMO+3 are ?* and ?* orbital excitations.The ?* orbital excitation is generally concentrated at the benzene ring and the ?* orbitals are generally oxygen or nitrogen atoms.Through the simulation of molecular docking,it was found that the docking of docetaxel molecules with tubulin are mainly focused on three drug targets,which we here named N1,N2,N3 sites.Through the literature review,it was found that the N2 site are highly consistent with the docetaxel drug targets reported in the known literature,but N3 has not been reported.We believe that the main reason for finding the N3 site lies in our previous systematic analysis.For all the lowest energy structures on the potential energy surface,the 31 structures with the lowest energy on the potential energy surface that we calculated using the density functional theory were obtained from our initial calculations in this study.It has not been previously reported in the literature.one docetaxel structure was stacked at the N1 site,nine taxanes at the N2 site,and twenty-one docetaxel at the N3 site.The key residues at the N2 site are Arg369,Leu371,Leu217,Phe272,Pro274,Leu219,Lys218,Pro360,Asp226.The key residues of the N3 site are Lys299,Arg215,Gln294,Leu275,Thr216,Glu290,Pro274,and Thr276,and the key residues of the N3 locus are analyzed in accordance with the lock-key theory,amino acid residues can form pocket-wrapped docetaxel.We believe that the main reason for finding the N3 site due to analysis of the previous system and explores all the stable structures on the potential energy surface of docetaxel.We performed further molecular dynamics simulations on the structures with better binding energy at the N2 and N3 sites.The results showed that the RMSD of the docetaxel with tubulin and the RMSD of the ligand itself of N3 site were superior to those of the N2 site.At the end of the article,we analyzed the Solvent Accessible Surface of docetaxel and paclitaxel,it is proved that the water solubility of docetaxel is better than paclitaxel.