What research contents are used in the course of medicinal chemistry to find safe and effective drugs?

New methods and advantages of drug discovery

According to the methods and technical characteristics adopted in drug research, the whole process of drug research can be divided into three main stages: drug discovery stage; Preclinical research of drugs; Clinical research of drugs. In the past, the discovery of drugs was limited to the screening of natural product extracts or finding clues from the patents of compounds. The synthesis of compounds only produced one compound at a time and only one reaction occurred at a time, which was very inefficient.

Introduction to Chemical Genetics

Chemical genetics is the bridge and link between genome and new drug research. It refers to the use of small molecular compounds with high specificity for some target proteins for gene function analysis and discovery of new drug lead compounds. Chemical genetics is a combination of combinatorial chemistry, genomics, protein genomics, molecular biology, pharmacology and other related technologies. With small chemical ligands with biological activity as probes, it studies the genes closely related to human diseases and the biological functions of protein, and provides high affinity drug lead compounds for new drug development.

The so-called chemical genetics drug discovery model is to find out the mechanism of disease occurrence and prevention at the cellular and molecular levels through functional genome research, find and confirm the target of drug action, and then search for drugs purposefully. The general procedures of drug discovery model in chemical genetics include target discovery, combinatorial chemical synthesis and Qualcomm screening.

Second, the key processes and advantages of the drug discovery model in chemical genetics.

1. Target discovery and drug design

Finding drug targets is the first step in the development of new drugs. The research results of human genetic engineering provide a lot of information for revealing the mechanism of human diseases. These disease-related genes or proteins can be used as potential drug targets. Using the corresponding relationship between gene and protein, the function of protein was analyzed, and what diseases were identified. Protein was purified and crystallized, and the structure of protein was determined by X-ray diffraction technology, so as to find the target of drug action.

At present, some genomics technologies provide opportunities for determining the best target of drugs. These technologies can be divided into: the global strategy of identifying pathogenic proteins and the target-specific strategy of partially characterizing pathogenic proteins. The former focuses on the identification and sequence analysis of drug targets, including computer homology calibration, differential gene expression analysis and total protein group analysis; The latter gives a reasonable explanation of gene function, including gene knockout, antisense mRNA and ribozyme inhibition, and computer simulation to predict the structure and function of gene products. In the activity detection and clinical research of disease cells or animal models, we can further understand the relationship between target and disease, realize the functional analysis of target gene or protein, and reveal the mechanism of disease and its treatment at the molecular level.

After defining the function and three-dimensional structure of the target biological macromolecules, the design of drug molecules can be started. With the development of computer science, advanced graphic workstations have appeared, which makes many new methods of drug molecular design develop rapidly. In 1990s, drug molecular design has become a practical tool involving all aspects of drug research and a core technology of innovative drug research. According to statistics, due to the intervention of molecular simulation and computer-aided drug design, the cycle of drug research and development has been shortened by 0.9 years.

Drug design methods can be divided into two categories: drug design based on small molecules (LBDD) and drug design based on receptor biomacromolecule structure (SBDD). LBDD is mainly based on the analysis of the relationship between the structure, physical and chemical properties and activities of existing drugs, and establishes a quantitative structure-activity relationship or pharmacodynamic group model to predict the activities of new compounds. According to the three-dimensional structure (crystal structure, nuclear magnetic resonance structure, low temperature electron microscope structure or computer simulation structure) of biological macromolecules (protein, nucleic acid, etc.). ), SBDD established the three-dimensional structure of the small molecule-receptor complex through theoretical calculation and molecular simulation, predicted the interaction between the small molecule and the receptor, and designed new molecules complementary to the receptor on this basis.

2. Combinatorial chemical synthesis

Combinatorial chemistry was originally produced to meet the demand of Qualcomm mass spectrometry screening technology for a large number of new compound libraries. It provides a material basis for Qualcomm screening, expands the scope of drug screening, and meets the requirements of rapid screening in chemical genetics. Combinatorial chemistry can synthesize a large number of organic molecules through a reliable chemical reaction system. According to the three-dimensional structure of the same receptor macromolecule, different lead compounds can be designed, and each lead compound can be used as a scaffold. Then the structure of the scaffold was modified, and different groups and molecular fragments were used to "extend" from different parts of the scaffold to different directions of the receptor, thus obtaining different compounds. In the process of drug screening, sample banks with different molecular structures can be used to screen different diseases and different models.

One of the earliest examples of combinatorial synthesis in drug discovery is peptide library synthesis described in an article published by Lilly Research Laboratory. Later, it was used to develop potential inhibitors of HIV protease pentapeptide. In addition to the synthesis of peptide libraries, combinatorial chemistry has also made great progress in the synthesis of other compound libraries. Since the development of combinatorial chemistry, after more than ten years of development, the greatest contribution is to provide a brand-new research thinking mode, that is, combinatorial mode. The basis of combinatorial chemistry is how to choose the most ideal molecules from different chemical libraries.

The synthesis of combinatorial chemistry library usually adopts solid-state chemistry technology. Solid-phase synthesis technology includes four parts: (1) stationary phase; (2) a linking group; (3) selective protection and deprotection strategy of active functional groups; (4) Chemical reaction and optimization of conditions. In addition to solid-phase chemical synthesis, combinatorial chemistry sometimes uses liquid-phase method. There are suitable chemical conditions, such as high yield or simple liquid-liquid extraction to obtain products, and liquid-phase compound library synthesis is also extremely suitable.

The organic combination of combinatorial chemistry and the corresponding screening method-Qualcomm screening technology has promoted the development of new drug discovery and development, and has become the core technology in the process of new drug discovery and development. Especially, the introduction of small molecular compound library makes combinatorial chemistry more practical in the field of drug discovery.

3. Qualcomm screening

Qualcomm shielding is a new technology developed in the late 20th century. It has the characteristics of rapidity, trace, high specificity, high sensitivity, high automation and full utilization of drug resources, and is often used in combination with combinatorial chemistry. HTS is the key technology of chemical genetics technology platform, which provides a new way for drug discovery and improves the speed of drug screening. For example, the chemical spatial physical constants of the lead compounds of adrenergic G protein-coupled receptor (GPCR) identified by functional ultra-Qualcomm screening (uHTS) were compared with the parameters of the known compounds regulating the same target in MDL drug database (MDDR), which showed that the new lead compounds were different from the previous modulators in chemical space and showed new target functions, which provided the only alternative lead compound structure for drug discovery and target confirmation.

In Qualcomm, drug screening adopts cellular and molecular screening models. The results screened by these models should be analyzed according to specific conditions and verified by other necessary testing methods:

(1) Interaction between samples and targets. The therapeutic effect of drugs is mostly due to the combination of drugs with specific sites (targets) of biological macromolecules in the body. The drug interacts with the target to realize mutual combination. According to the principle of intermolecular interaction, a screening model can be established to screen out samples with affinity for specific targets.

(2) Effect on enzyme activity. When screening enzyme inhibitors, compounds with affinity can be screened according to the principle of intermolecular interaction, and compounds that affect enzyme activity can also be screened according to enzyme activity as a detection index. Using enzyme activity (observing the decrease of reaction substrate or the increase of reaction product) as an observation index can directly explain the function of drugs. This screening model is widely used in Qualcomm screening.

(3) Effects on cells. Taking the whole cell as the target of drug action, the influence of screened samples on the whole cell was observed. This mode of action may be through a specific target, or it may act on multiple targets, and its effect is obtained under the condition of whole cell, which can reflect the whole cell's response to drug action.

Qualcomm screening method is generally used for the following steps of drug discovery and development:

(1) Primary screening and secondary screening. After the initial screening, the active compounds were screened out, and the same model was re-screened with a series of concentrations to clarify its action characteristics, action intensity and dose-effect relationship, so as to find the active compounds (samples).

(2) Deep screening. On the basis of primary screening and secondary screening, different but related molecular and cell models were used to further screen the obtained samples, including proving the selectivity and cytotoxicity of the samples.

(3) Confirmatory screening. The lead compounds obtained by in-depth screening or the compounds with the best activity selected after optimization were studied more deeply and extensively, including pharmacological action, drug metabolism process, general toxicity and so on, in order to determine their development prospects. Samples that meet the requirements are identified as drug candidate compounds and enter the development research program, that is, preclinical research, to prepare necessary data for clinical research.

Third, summary.

As a new drug discovery method, chemical genetics drug discovery model combines combinatorial chemistry, Qualcomm screening, computer-aided drug design, protein omics and other technologies to speed up drug discovery. In addition, chemical genetics, as a new drug research and development model, has unique advantages in the research of small molecular drugs and promotes the development process of small molecular drugs. Drug discovery, as the first step in drug research, has improved its efficiency and brought the whole medical level and the development of the pharmaceutical industry to a new level.

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