Molecular docking research is a method of applying mathematical, biological and computer models to predict the affinity of small molecules for specific receptors. Strictly speaking, molecular docking is a computer-based analysis that can predict the binding affinity of new chemical entities (NCEs) or drugs based on their chemical structure. Molecular docking research combines advances in molecular biology, biotechnology, bioinformatics, mathematics, chemistry and modeling, and computer science to improve the predictive capabilities of docking software.
The evaluation of the safety and effectiveness of various drugs is still mainly based on animal experiments, but unfortunately, there are many serious problems in animal experiments, such as the problem of drug efficacy after long-term use. Due to the short life span (4-5 years), the animal's Chronic effects cannot be studied. However, in contrast, the average life expectancy of a normal person is 70 years. Therefore, the results observed in animals are difficult to extrapolate to humans. In order to observe these pharmacological effects, the drug dose received by animals far exceeds the dose that humans are exposed to in real life. In experiments, this higher dose of the drug usually showed some signs of overdose, which caused questions about accuracy and reliability. In addition, in accordance with regulatory guidelines, it will be a very challenging task to study setting higher doses of drugs to lower doses and obtaining reliable results.
Molecular docking is a method for evaluating the preferred orientation of one molecule to another when it binds to each other to form a stable complex. It is one of the most commonly used methods in structure-based drug design. Because molecular docking can predict the binding conformation of small molecule ligands and target binding sites, this technology can be used to screen biologically active compounds in the early stages of drug development. Molecular docking research can play an important role in studying the PK and PD of drugs. In kinetic studies, people can predict the interaction of drugs with various metabolic enzymes, and pharmacologists can understand how NCEs are metabolized in the body. Once the drug reaches the target site, it will bind to the specific target and perform physiological functions. Drug-receptor complexes are the focus of various physiological and pharmacological effects. Molecular docking can help predict the affinity and binding properties of drugs to specific targets.
The docking algorithm predicts several orientations of the ligand at the binding site. Several different docking algorithms have been developed, and each docking algorithm has its own advantages and disadvantages. These docking programs use one or more specific search algorithms to predict the binding mode of the complex. The main key point of the docking algorithm development is the accuracy of docking. The scoring function is an approximate method for estimating binding affinity, and is the main tool for leading optimization of virtual screening results. Many methods can be used to assess the binding affinity between a protein and a ligand in a given complex. The low binding energy of the ligand protein complex indicates the high stability of the complex, which means that the contact time between the ligand and the receptor is more in this specific conformation. It is recommended to adopt the conformation of the ligand protein complex in this specific direction to obtain more accurate results.
Molecular dynamics (MD) simulation has become a very valuable tool for exploring protein structure. These simulations can be used before and after the protein is docked with a specific ligand to optimize its structure and explain the flexibility of the protein. For the optimization of the docking complex, the binding free energy can be calculated to more accurately evaluate the affinity between the ligand and the receptor. MD simulation is used to explore the stability and conformational flexibility of all protein and ligand systems. However, according to the simulation of MD experiments, entering the binding pocket sometimes causes the conformational change of the binding site.