What is Molecular Docking Technology?

Molecular docking technology is a kind of technology to recognize and predict the structure of receptor-ligand complex through the simulation of molecular geometry and intermolecular forces supported by stoichiometry and other disciplines. The mechanism of molecular docking can be explained by the "lock & key principle" of the interaction between ligands and receptors.

Fig 1. The lock & key model of receptor-ligand

The interaction between ligand and receptor is a process of molecular recognition, including electrostatic interaction, hydrogen bonding, hydrophobic interaction, van der Waals interaction and so on. The binding pattern and affinity between the two can be predicted by calculation.

Steps of Molecular Docking

Molecular ligand is a relatively mature method for direct drug design in recent years. The general research steps of molecular docking are as follows:

1. Preparation of receptor structure: download or construct three-dimensional structure of receptor molecule through database;
2. Preparation of drug molecules: 3d structure of drug molecules can be constructed by downloading from crystal database or molecular simulation;
3. Pre-docking processing: processing ligand and receptor and selecting target;
4. Task submission: Select appropriate docking software and parameters for different systems;
5. Analyze and graph results.

Types of Molecular Docking

1. Rigid body docking: conformation of the research system does not change during docking. It is suitable for studying relatively large systems, such as the docking between proteins and nucleic acids.
2. Semi-flexible docking: In the docking process, the conformation of the research system, especially the ligand, is allowed to change within a certain range. Suitable for handling docking between large and small molecules. In the docking process, the conformation of small molecules is generally changeable, but most are rigid and cannot be changed.
3. Flexible docking: In the docking process, the conformation of the research system can change freely. Generally, it is used to accurately consider the recognition between molecules. Because the conformation of the system can be changed during the calculation, the amount of calculation is the largest.

Problems in Molecular Docking

1. How to find the best combination location
   This involves the problem of docking optimization. Both the substrate molecule and the receptor molecule are free to rotate and move, and the conformation of the two molecules also changes, so the possible combination mode between them is very complex. The commonly used optimization docking methods include genetic algorithm, simulated annealing and taboo search.
2. How to determine the binding strength between docking molecules
   It involves the prediction of binding ability between target and receptor molecules and the calculation of binding free energy.

Basic Types of Molecular Docking

1. Global molecular docking method: a specific search algorithm is used to investigate the energy of ligand molecules at the binding site of the receptor and find the optimal binding method.
2. Based on fragment docking method: the ligand molecule is regarded as a collection of several fragment structures. First, one or several basic fragments are put into the binding pocket, then the rest of the molecule is constructed at the active site, and finally the theoretical optimal binding method is obtained.

Application of Molecular Docking

Molecular docking can study the detailed interaction between ligand and receptor, predict its binding mode and affinity, and also be used to discover and optimize drug lead molecules, thus realizing structure-based drug design. The essence of molecular docking is a process of mutual recognition between two or more molecules, which involves spatial matching and energy matching between molecules. According to the energy matching level, the initial optimal intermolecular structure and binding mode are obtained. The application of molecular docking in drug research includes:

1. Explore specific modes of action and binding configurations of small and large molecule receptors for drugs;
2. Screening lead drugs that can bind to the target;
3. Explain the reasons for the activity of drug molecules;
4. Guide rational optimization of drug molecular structure.

In addition, molecular docking studies can play an important role in studying PK and PD of drugs. In pharmacokinetic studies, one can predict drug interactions with various metabolic enzymes, and pharmacologists can understand how NCEs are metabolized in the body. Once a drug reaches its target site, it binds to a specific target and performs a physiological function. Drug-receptor complexes are the focus of a variety of physiological and pharmacological actions, and molecular docking can help predict drug affinity and binding properties for specific targets.