Drug screening refers to the process of evaluating the biological activity, pharmacological effect and medicinal value of substances (samples) that may be used as drugs by adopting appropriate methods.Drug screening is screening at 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 areGenomics、Proteomics、Metabonomics、Computational biology、Biochip technology、Microfluidic chip technologyIt is a process of drug optimization within a certain selectable range.Therefore, drug screening includes prescription screening in the process of new drug research, and selecting drugs that meet the requirements according to specific purposes.
narrow sense: Screening specifically refers to the use of experimental techniques.[1]
Activity experiment
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Drug screening is the process of testing and obtaining drugs with specific physiological activities in the modern drug development processchemical compoundA step of, refers to the process of selecting compounds with high activity for a specific action target from a large number of compounds or new compounds through standardized experimental means.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 on new compounds have gradually changed from early validation experiments to screening experiments, namely the so-called drug screening.
As screening, the physiological activities of different compounds need to be compared horizontally, so the experimental scheme of drug screening needs to be standardized and quantified.With the development of combinatorial chemistry and computational chemistry, people began to have the ability to synthesize and separate a variety of compounds on a large scale in a short time. Therefore, drug screening has gradually become one of the main ways to find lead compounds in the modern process of new drug development.[1]
Filter model
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Screening model is the pharmacology applied in drug screening experimentExperimental modelBecause drug screening requires the experimental scheme to be standardized and quantified, animal experiments commonly seen in traditional pharmacological experiments are rarely used in drug screening. According to different experimental models, drug screening can be divided into biochemical level screening and cell level screening.
Biochemical drug screening uses the target design experiment of the drug to be developed. Generally speaking, this target is a protein with specific physiological functions, such as enzymes and receptors. In addition, some DNA with well-defined coding functions are increasingly becoming the target of drug action.After the candidate compounds are mixed with the target, the interaction between the compounds and the target can be quantitatively determined by enzyme-linked immunosorbent assay, fluorescence color development, nuclear magnetic resonance and other methods, which becomes the basis for screening compounds.Cell level drug screening is a drug screening model that is more close to physiological conditions. Its model is the target cells for the proposed drug action. The required cells are obtained by using cell culture technology, and these cells interact with candidate compounds. The action ability of compounds is measured through detection technology similar to biochemical level screening, so as to screen compounds.
Biochemical drug screening is relatively simple and low cost. However, since the role of drugs in the body does not depend on the degree of interaction with target enzymes, absorption, distribution, metabolism and excretion will have a great impact on the role of drugs. A thin membrane can block many candidate compounds from becoming drugs,As a result, there are more uncertain factors in drug screening at the biochemical level, and the screening error rate is higher.Cell level drug screening models are closer to physiological conditions and have higher screening accuracy. However, cell models need to be established. The operation is more complex, the cost is higher, and the parallelism between data is poor. In addition, due to technical limitations, some targets cannot be used for cell level drug screening.[1]
classification
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High throughput screening
High throughput screening was initially accompanied byCombinatorial chemistryIt is a drug screening method.In the late 1990s, the emergence of combinatorial chemistry changed the way of obtaining new compounds. People can simultaneously synthesize a large number of compounds in a short time with fewer steps. In this context, high-throughput screening technology 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, which is not only used for screening compounds in combination chemical libraries, but also more used for screening existing compound libraries.All major drug manufacturers in the world have established their own compound libraries and high-throughput screening institutions to screen compounds with potential to form drugs in a comb style.
A high-throughput drug screening system includes micro and semi micro pharmacological experimental models, sample library management system, automated experimental operating system, high-sensitivity detection system, and data acquisition and processing system. The operation of these systems ensures that the screening system can search for a large number of candidate compounds in parallel.High throughput screening technology combines the knowledge and advanced technology of molecular biology, medicine, pharmacy, computing science, automation technology and other disciplines, and becomes the main way of drug development today.The complete high-throughput screening system is also called "drug screening robot system" because of its high integration and automation.[1]
Virtual drug screening
Virtual drug screeningIt is another direction of the development of drug screening technology. Because the physical drug screening needs to build a large-scale compound library, extract or cultivate a large number of target enzymes or target cells necessary for experiments, and needs complex equipment support, it requires a huge amount of money to conduct physical drug screening. Virtual drug screening is to simulate the process of drug screening on a computer,Predicting the possible activity of compounds, and then conducting targeted solid screening for compounds that are more likely to become drugs, can greatly reduce the cost of drug development.
According to the calculation principle, virtual drug screening can be divided into two categories: screening based on small molecule structure and screening based on drug action mechanism,This screening technology is essentially a database search technology;The latter mainly uses molecular docking technology. To implement this screening, it is necessary to know the molecular structure of the drug target, calculate the binding ability of small molecules in the compound library to the target through molecular simulation, and predict the physiological activity of candidate compounds.Establishing a reasonable pharmacophore model, accurately determining or predicting the molecular structure of target proteins, and accurately and rapidly calculating the free energy changes of the interaction between candidate compounds and targets are the key to virtual drug screening, and also the bottleneck to limit 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.[1]
