Theoretical Investigation Of The Structures Of AT1 Antagonists

In present work, a series of computational chemical methods were employed to investigate the conformers and properties of AT1 antagonists valsartan, V8, V12 and BZI8. This thesis consists of three chapters,including (1) introduction of the AT1 receptor and its antagonists; (2) Computational chemical methods; (3) theoretical investigation of the AT1 antagonist valsartan; (4) Quantum chemical investigation of the AT1 antagonists V8, V12 and BZI8.Firstly, I briefly review the researched background of AT1 antagonists and interaction mechanism between receptors and antagonists.Furthermore, the theory applied in this work, including the molecular dynamics (MD) simulation and quantum chemistry methods (semi-empirical (SE) method and density function theory (DFT) ), were introduced.In the third chapter, the two conformations of valsartan are obtained with MD, SE and DFT methods. At first step, the initial structure was searched by short-time MD simulation, and then systemically searches were applied for five important dihedral angles with SE and DFT methods. The obtained structures were consistent with the experimental chemical shift and NOE data, and this calculation also gave a reasonable explanation for the experimental dynamics data. In the last chapter, starting from structure of Mavromoustakos et al. which obtained from MD and Monte Carlo (MC) method, the equilibrium geometry structures of three AT1 antagonists, V8, V12 and BZI8, were studied with DFT methods. The chemical shifts of the protons for the there compounds were also calculated. The computational results are consistent with the experimental data of ROE and the 1H NMR spectrum.