Molecular Dynamics Simulations And Free Energy Calculations For Drug Design

With the rapid development of computer technology, computer aided molecular modeling has become a very important and active task in chemistry, biochemistry and molecular biology. In this dissertation, molecular dynamics simulations, quantum mechanical ab initio calculations, together with quantum mechanical/molecular mechanical (QM/MM) method have been used to study the brain imaging agents of 99mTc-N2S2 complexes and HIV-1 integrase inhibitor 1-(5-(2-Chloroindol)-3-yl)-3- hydroxy-3-(2H-tetrazol-5-yl)-propenone (5ClTEP).Radical brain imaging agents play important roles in the medical treatment of brain diseases. In this study, we found that the brain uptakes of the 99mTc-N2S2 complexes were influenced by their hydrate free energies. The MD simulations showed that the differences between the brain uptakes of bisaminodithiol (BAT) and monoamino-monoamide dithiol (MAMA) complexes were determined by their relative hydrate free energies. The calculations of self-consistent reaction field (SCRF) method illustrated that the brain uptakes of the complexes relied on their absolute hydrate free energies. Furthermore, the QM/MM results approved that MAMA complexes were more stable than BAT complexes in aqueous solutions, hence the MAMA complexes were difficult to cross the the intact blood brain barrier (BBB) and had lower brain uptakes than BAT complexes. The BAT complexes are one kind of the promising brain imaging medicines.The study of HIV integrase inhibitors is important in the research of anti-AIDS medicines. The MD simulations showed that the key part of the inhibitor 5ClTEP is thearyl (-diketo function group, which was bounded to the active site of the HIV-1 integrase (residue Glu152), and achieved inhibiting effect in the HIV-infected cells. The existence of Mg2+ cation bought a stronger inhibiting effect to the inhibitor, and this experimental result was approved by our MD simulations, which showed that the inhibitor 5ClTEP cooperated with Mg2+ cation in the stability of the whole complex system. The tetrazol and indole function groups of 5ClTEP were also helpful in the stability of the integrase-inhibitor complex system, however, the simulating results showed that the tetrazol group was more important than the indole ring, which would make help in further drug design of anti-AIDS medicines...