Drug screening refers to the process of evaluating biological activity, pharmacological effects and medicinal value of substances (sampling) that may be used as drugs using appropriate methods. Drug screening is a screening at the biochemical and cellular levels.
Drug screening is divided into high-throughput and virtual drug screening.
Generalized: It is aimed at specific requirements and purposes, through appropriate methods and technologies, the main technologies include genomics, proteomics, metabolomics, computational biology, biochip technology, microfluidic chip technology and other methods. Within the selectable range of , the process of drug optimization is carried out. Therefore, drug screening includes prescription screening in the process of new drug research, and selection of drugs that meet the requirements for specific purposes.
Narrow definition: Screening refers exclusively to the use of experimental techniques.
Activity test
Drug screening is a step in the modern drug development process to test and obtain specific physiologically active compounds. It refers to the process of selecting compounds with higher activity on a specific target from a large number of compounds or new compounds through standardized experimental methods. . The process of drug screening is essentially the process of conducting pharmacological activity experiments on compounds. With the development of drug development technology, the physiological activity experiments of new compounds have gradually changed from early verification experiments to screening experiments, the so-called screening experiments. Drug Screening.
As screening, the physiological activities of different compounds need to be compared horizontally, so the experimental protocol of drug screening needs to have the characteristics of standardization and quantification. With the development of combinatorial chemistry and computational chemistry, people have the ability to synthesize and isolate a variety of compounds on a large scale in a short period of time. Therefore, drug screening has gradually become one of the main ways to discover lead compounds in the modern new drug development process.
filter model
The screening model is a pharmacological experimental model used in drug screening experiments. Since drug screening requires the experimental protocol to have the characteristics of standardization and quantification, animal experiments commonly used in traditional pharmacological experiments are seldom used in drug screening. drug screening can be divided into biochemical screening and cellular screening.
Drug screening at the biochemical level is designed with the target of the drug to be developed. Generally speaking, the target is a protein with specific physiological functions, such as enzymes and receptors. In addition, some DNAs with clear functions are also becoming more and more important. become the target of drug action in many places. After the candidate compound is mixed with the target, the interaction between the compound and the target can be quantitatively determined by methods such as enzyme-linked immunosorbent assay, fluorescence color development, and nuclear magnetic resonance, thereby becoming the basis for screening compounds. Drug screening at the cellular level is a drug screening model that is closer to physiological conditions. The model is to design the target cells for drug action, use cell culture technology to obtain the desired cells, and interact with these cells with candidate compounds. Compounds are screened by screening analogous detection techniques to determine their ability to act.
The drug screening operation at the biochemical level is relatively simple and the cost is low, but because the effect of the drug in the body does not only depend on the degree of its interaction with the target enzyme, the absorption, distribution, metabolism, and excretion will all have a great impact on the effect of the drug. Only a thin cell membrane can block the way for many candidate compounds to become drugs, so there are more uncertainties in drug screening at the biochemical level and a higher false screening rate. The cell-level drug screening model is closer to physiological conditions, and the screening accuracy is higher, but the cell model needs to be established, the operation is more complicated, the cost is higher, and the parallelism between data is poor. Cell-level drug screening cannot be performed.
Classification
High-throughput screening
High-throughput screening was originally a drug screening method accompanying combinatorial chemistry. In the late 1990s, the advent of combinatorial chemistry changed the way humans obtain new compounds. People can simultaneously synthesize a large number of compounds in a short period of time with fewer steps. In this context, the technology of high-throughput screening came into being. High-throughput screening technology can screen a large number of candidate compounds in a short time. After development, it has become a relatively mature technology. It is not only used for compound screening of combinatorial chemical libraries, but also more applied to existing compound libraries. filter. The world’s major drug manufacturers have established their own compound libraries and high-throughput screening institutions to screen the compounds with the potential to form drugs.
A high-throughput drug screening system includes micro and semi-micro pharmacological experimental models, a sample library management system, an automated experimental operating system, a high-sensitivity detection system, and a data acquisition and processing system. The operation of these systems ensures that the screening system can operate in parallel. Search a large number of candidate compounds. High-throughput screening technology combines the knowledge and advanced technology of molecular biology, medicine, pharmacy, computational science and automation technology, and has become the main way of drug development today. The complete high-throughput screening system is also called “drug screening robot system” due to its high degree of integration and automation.
Virtual Drug Screening
Virtual drug screening is another direction in the development of drug screening technology. Since physical drug screening requires the construction of a large-scale compound library, the extraction or cultivation of a large number of target enzymes or target cells necessary for experiments, and the support of complex equipment, the physical drug screening is carried out. Drug screening requires huge investment. Virtual drug screening simulates the process of drug screening on a computer, predicts the possible activity of compounds, and then conducts targeted physical screening of compounds that are more likely to become drugs. Dramatically reduce drug development costs.
According to the computational principle, virtual drug screening can be divided into two categories: small molecule structure-based screening and drug action mechanism-based screening. Model, according to the model to search the compound database, this screening technology is essentially a database search technology; the latter mainly uses molecular docking technology, the implementation of this screening needs to know the molecular structure of the drug target, and calculate the compound through molecular simulation. The ability of the small molecules in the library to bind to the target predicts the physiological activity of the candidate compound. Establishing a reasonable pharmacophore model, accurately determining or predicting the molecular structure of the target protein, and accurately and quickly calculating the free energy change of the interaction between candidate compounds and the target are the key to virtual drug screening and the bottleneck that limits the accuracy of virtual screening. Although the accuracy of virtual screening needs to be improved, its fast and cheap characteristics make it one of the most rapidly developing drug screening technologies.
