Development Of Drug Discovery Strategies And Its Applications In Leukaemia

In this paper, mainly through the view of three parts, we had explain the strategies and biological activity test of drug discovery in different aspect, and make contributions to the traditional drug development to some extent.The first part of this paper is mainly about the application of privileged structure in drug discovery. The lead compounds is the first step in the process of drug development, and also is the key to the current drug development. Lead compounds for drug research is becoming an hot spot in this field. Since 1988, Evans put forward the concept of privileged structure, privileged structure have had a significant impact in modern drug discovery, and cause a great scientific guiding significance.Privileged structure refers to a fragment which jointly owned by a class of chemical compounds, and the chemical compounds which derived from the privileged structure can interact with diverse biological receptors, such as protein, this always accompanied by good biological function. So in the process of modern drug research and development, the method based on privileged structure increase the ratio of active molecules to a certain extent. Starting from an privileged structure, derive a series of lead compounds which have good affinity for different biological targets. Meanwhile, allosteric drug also become a hot spot in drug development. Allosteric drug can change the structure of receptor proteins and further influence their biological function, inhibiting the occurrence and development of disease. For the first part of this paper, we have extracted privileged structures from Allosteric Database(mdl.shsmu.edu.cn/ASD), we hope to find some new clues and new opinions from allo-privileged structure in drug discovery, and make a significant guidance for drug development.The second part of this paper is mainly about the prediction of human clearance. Human clearance(CLHuman) is a critical pharmacokinetic parameter, There are many ways to predict the Human clearance, One of the most widely used approaches to derive CLHuman is interspecies allometric scaling method, namely, extrapolation of animal data to human clearance. Allometric scaling method is usually based on some physiological parameters as well as correction factors. Actually, physiological parameters and correction factors also reflect the difference between humans and animals for a given drug. At the same time, a great number of interleaving molecular properties of drug have complex effects on the characterization of CLHuman, so the model with mixed animal data and molecular descriptors was constructed in this study. Genetic algorithm(GA) was employed to select molecular descriptors and several support vector machine(SVM) models based on the clearance data of three species and the molecular descriptors were established and validated. These models and modeling method can be used to predict CLHuman for the compounds with various properties and should be considered as an improved allometric scaling method in drug research and development.The third part of this paper is mainly about the discovery of a series of small molecule inhibitors of NHR2. NHR2 is a leukemia pathogenic factor which discovered in recent years. First, by the means of computer acid drug discovery, and based on the co-crystal of NHR2-N2 B released in 2014, and we choose a accurate site, and screened a series small compounds from 1.5 million molecules derived from SPECS(http://www.specs.net) and Chemdiv(http://www.chemdiv.com), then we tested biological activity of each compound, through our effort, we selected several high-affinity drug lead compounds for NHR2-N2 B complex. On this basis, we further study their interaction mechanism, and states the mode of interaction between small compound and NHR2 in structure-activity relationship. Afterwards we found a new site and some small molecules for leukemia, and provide certain scientific view point for the study of leukemia.