Theoretical And Methodology Study On Computer-aided Design Of Phosphatase Inhibitors

Phosphatase is a critical enzyme in regulating the signal transduction in cells. It has been proved to be a useful target for the therapy of cancer, diabetes and many other diseases.α-Fluorination effect existing in the active sites of the phosphatase inhibitor, which enhances the activity the inhibitors by 3 magnitudes, is an important phenomena and the underlying reasons are still undetermined. In this dissertation, we give an investigation to the theory and methodologies related to theα-fluorination effect and the drug design work. The content mainly covers four aspects, which are the ab initio calculation study on theα-fluorination effect, the program design of Monte Carlo (MC) method based on the TEAM all-atom force field, factors analysis influcing the efficiency of free energy perturbation method based on the molecular simulation calculation of Henry's Law Constant (HLC) with Widom insertion method, binding mode and binding affinity calculation with molecular dynamics simulation (MD). Investigation results show that:1. The introduction of fluorine atoms on theα-position of the inhibitor active site mainly affects the charge distribution of the local sites. Fluorine is not a good hydrogen bond acceptor. Solvation effect calculation with DPCM and IEFPCM model was found to be good and important to the study.2. Four basic MC moves were designed for the MC program based on TEAM all-atom force field. They proceed successively along the Markov chain. The validation results tell that it works.3. Widom program was designed for 16 cases, which can be generated by combine the solvent sampling methods (MC or MD), the solvent ensemble (NVT or NPT), solute particle insertion method (random or grid insertion) and the rotation strategy (YES or NO). Calculation results give a strong hint that the free energy perturbation method can give a good results and enough attention should be paid to the sampling efficiency. United-atom force field is preferred by the sampling in some cases.4. The binding mode and binding affinity calculation prove that the electrostatic part of the molecular interaction energy play the key role when the inhibitor binding phosphatases. The difluorinated inhibitor posess the similar activity to the enzyme substrate, and is much more active than the non-fluorinated compound. Therefore, when developing this kind of inhibitors , we should pay more attention to the charge effect brought by the introduced atoms, but no hydrogen bonding effects.