Evaluation Of Drug Metabolism Properties (adme) Of Early And Rapid Prediction Technology Research And A Series Of Compounds

With the development of Combinatorial Chemistry and high throughput screening technology, the speed of drug discovery has improved dramatically. However, it has been estimated that approximately 40% of compounds have failed in the past due to problems in pharmacokinetics and drug delivery. The objective of this paper was to in pace with the latest development of international pharmaceutical industry and to accelerate the national drug research. Surported by two foundations, we have taken the lead in constructing a systematic screening system and established the key technology to speed up the development of drug discovery.This dissertation consists of two parts. Firstly, in accordance with the principle of rapidness, simplicity, generality and effectiveness, an integrated screening ADME properties system including three phases of in silico, in vitro and in vivo was constructed. Secondly, we evaluated several series of novel compounds by using the platform and validated the relationships among different models.Model Construction:VolSurf and Pallas soft wares were applied in computational prediction. As the first step, we validated the predictive ability of these soft wares by using the known compounds published on literature or from our past experiments. Liner regression analysis showed a reasonable correlation (r~2=0.8998, r~2=0.7714). A new two components partial least squares discriminant analysis (PLS) model for the prediction of P-glycoprotein-associated ATPase activity of drugs was built by using VolSurf compute theoretical molecule descriptors derived from 3D molecule interaction fields. The results effectively investigated that properties associated with the volume, polarizability, and hydrogen bond could have important impact on the P-glycoprotein-associated ATPase activity.On in vitro ADME screening system, Caco-2 cell model and PAMPA model were built to evaluate the permeability, and liver microsome model was developed to appraise the metabolic stability. We optimized the experimental conditions to standardize the models. In order to increase the in vitro throughput, 5 in 1 approach in PAMPA and liver...