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A Brief Introduction to Molecular Docking

Molecular docking is the process of mutual recognition between two or more molecules through geometric matching and energy matching.

In the process of drug molecule’s pharmacodynamic reaction, the drug molecule and the target enzyme are bound to each other. First, the two molecules need to be close enough to adopt the appropriate orientation, so that the two molecules meet each other in the necessary part, interact, and then pass the appropriate to obtain a stable complex conformation, determine the correct relative position and orientation of the two molecules in the complex through molecular docking, and study the conformation of the two molecules, especially the changes in the substrate conformation during the formation of the complex. It is the basis for determining the mechanism of drug action and designing new drugs.

Molecular docking calculation is to place the ligand molecule at the active site of the receptor, and then according to the principles of geometric complementarity, energy complementation, and chemical environment complementation to evaluate the interaction between the ligand and the receptor in real time, and find the best combination mode. Because molecular docking considers the information of receptor structure and the interaction information between receptor and drug molecule, it is more reasonable than the drug design method that only starts from the ligand structure.

Principles of molecular docking

The theoretical basis of molecular docking

In molecular docking, the “lock” and “key” are flexible, that is, the substrate molecule and the target enzyme molecule adapt to each other during the docking process to achieve a better match.

Complementarity and pre-organization are two important principles that determine the molecular docking process. The former determines the selectivity of the recognition process, and the latter determines the binding ability of the recognition process. Complementarity includes complementarity of spatial structure and complementarity of electrical properties.

In 1958, Koshland proposed the concept of induced fit in the molecular recognition process, pointing out that when the substrate and the receptor bind to each other, the receptor will adopt a conformation that can pass the substrate to achieve the best combination. This process is called the recognition process. The receptor and the substrate molecule organize the environment of the receptor in the receptor before the recognition, the lower their solvation ability, the better their recognition effect, the more stable the complex formed, this is the molecular recognition Pre-organization principle.

Classification of molecular docking methods

Molecular docking methods can be roughly divided into three categories according to different degrees of simplification: rigid docking, semi-flexible docking and flexible docking.

  1. Rigid docking: the conformation of the research system does not change, and the representative method is soft docking;
  2. Semi-flexible docking: allowing changes within a certain range, among which the most representative method is molecular docking;
  3. Flexible docking: a molecular docking method based on molecular mechanics and molecular dynamics in the docking process.

Rigid docking is suitable for investigating relatively large systems, such as between protein and protein and between protein and nucleic acid. Its calculation is relatively rough and the principle is relatively simple. Semi-flexible docking is suitable for handling the docking between small and large molecules. During the docking process, small molecules can change, but large molecules (such as target enzymes) are rigid. In drug design, especially in database search for basic molecular docking, semi-flexible molecular docking methods are generally used.

The flexible docking method is generally used to accurately investigate the recognition between molecules. Since the conformation of the system can be changed during the calculation process, flexible docking requires a long calculation time.

Important issues in molecular docking methods

The purpose of molecular docking is to find the best binding position between the substrate molecule and the receptor molecule. Therefore, molecular docking will face two important issues, how to find the best binding position and how to evaluate the bonding strength between docking molecules.

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