An Overview of Application of Molecular Docking in Pharmacology
About molecular docking
Molecular docking is a method of applying mathematical, biological and computer models to predict the affinity of small molecules to 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 drug development process is long and expensive, and the loss rate of NCE is very high, the incidence of disease is increasing year by year, and the emergence of drug resistance, all urge the speed of drug development. In order to save resources in the drug discovery and development process, molecular docking studies are widely used to predict the interaction of designed analogs with specific receptors. Applied to pharmacology, these methods can predict the affinity of the drug in the target-binding site and the interaction of the drug with specific metabolic enzymes to predict the pharmacokinetic properties of the drug and better understand the complexity of life systems.
There are currently a variety of docking methods that can be used to predict the interaction of molecules with specific receptors. Although some docking results have high scores, many compounds ended in failure in molecular dynamics simulations. If the molecular docking tool is used correctly, the safety and efficacy of the molecule can be evaluated very effectively. In order to ensure the accurate and effective application of the molecular docking model, it is necessary to understand the advantages, limitations and scope of application of the method, and to customize a suitable molecular docking research method for each problem according to the needs.
The application of molecular docking in pharmacology
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), animal 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 for researchers to set higher doses of drugs to lower doses and obtain reliable results.
Another issue is the cost of research. Animal safety and effectiveness research is very expensive, or it can cause moral and ethical issues. According to the FDA report, more than 90% of promising new chemical entities (NCEs) failed in human trials, possibly due to efficacy or safety issues. From the perspective of the pharmaceutical industry, in order to avoid failures in the middle and late stages of NCEs development, molecular docking research is mainly carried out in the early stages of the development process.
The situation of molecular docking research
Molecular docking is a method to evaluate 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.
Docking algorithm
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 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.
Selection and preparation of protein
The choice of protein plays a major role in the docking result. Due to the improvement of structure determination technology, the three-dimensional structure of a specific receptor is easily obtained in the protein database (PDB). The question is how to choose the structure of the protein? The protein structure can be selected according to the X-ray resolution and the conditions for obtaining the protein crystal structure. It is recommended to select a protein structure with a resolution less than 2 Å.
Once the protein to be studied is determined, the next question will arise. Can these protein structures be used directly? The answer is negative. If used directly, it will produce unexpected research results. It is usually necessary to prepare the protein by adding hydrogen ions and removing water molecules, and finally to minimize energy. If there is no crystal structure of the protein in the PDB database, then researchers can construct the protein structure through homology modeling, and verify the protein model through Ramachandran diagrams or other methods to improve the accuracy of prediction.
Selection and preparation of ligand
The ligand structure can be drawn in Chem draw software, or downloaded from PubChem chemical database or ZINC library. Before using these structures for docking, energy minimization should be performed.
Selection of molecular docking type
There are two main types of docking: rigid docking and flexible docking. In rigid docking, the protein and ligand are fixed, so the bond angle or length cannot be changed. The advantage of this method is that the docking speed is very fast, but it lacks its practical use because it ignores the conformational freedom of the ligand. While flexible docking allows the rotation of all the rotatable bonds of the receptor and ligand, but the flexible docking calculation requires a lot of time and computational effort. Therefore, a docking method between the two-semi-flexible docking came into being. The central idea of semi-flexible docking is to make the docking ligand flexible, while the macromolecular receptor is regarded as rigid. Taking into account the flexibility of the ligand molecule, it can also greatly save the amount of calculation, so it has been widely used. At present, this semi-flexible docking method can basically solve most research problems, and those “difficult diseases” that need in-depth research can be solved by molecular dynamics simulation.
Scoring function selection of molecular docking
The choice of the optimal docking scoring function depends on the stability of the ligand protein complex. How to choose a suitable docking conformation? The lower Gibbs free energy of the complex can indicate to a certain extent that the protein-ligand complex is relatively stable.
Verification of molecular docking
Molecular dynamics simulation (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 is 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.