Docking
From DrugPedia: A Wikipedia for Drug discovery
Docking is the identification of low energy conformation after binding of ligand molecule with target/receptor.The compound that bind strongly in the active site of target molecule and having minimum energy may be act as potential drug molecule.
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Mechanism of Docking
Docking can be divided into two separate problems. The search algorithm should create an optimum number of configurations that include the experimentally determined binding modes. These configurations are evaluated using scoring functions to distinguish the experimental binding modes from all other modes explored through the searching algorithm.
Search Algorithm
A rigorous searching algorithm would go through all possible binding modes between the two molecules.
Some common searching algorithms include:
- Molecular dynamics
- Monte Carlo methods
- Genetic algorithms
- Fragment-based methods
- Point complementary methods
- Distance geometry methods
- Tabu searches
- Systematic searches
Scoring Function
Current docking methods utilize the scoring functions in one of two ways. The first approach uses the full scoring function to rank a protein-ligand conformation. The system is then modified by the search algorithm, and the same scoring function is again applied to rank the new structure. In the alternative approach a two stage scoring function is used. A reduced function is used in directing the search and a more rigorous one is then used to rank the resulting structures.
Some common scoring functions are
- Force-field methods
- Empirical free energy scoring functions
- Knowledge-based potential of mean force
Types of Docking
- Molecular Docking
- Protein-Protein Docking
- Protein-Ligand Docking
Molecular Docking
Molecular Docking is referred to as small molecule docking. Molecular docking is a study of how two or more molecular structures, for example drug and enzyme or protein receptor, fit together. Molecular Docking is frequently used to predict the binding orientation of small molecule drug candidates to their protein targets in order to predict the affinity and activity of the small molecule.
Protein-Protein Docking
Protein-protein docking is the determination of the molecular structure of complexes formed by two or more proteins without the need for experimental measurement. The study of protein-protein docking was boosted by the rapid increase in available protein structures of the 1990s, and it has now been under intensive research for over a decade. Many proteins which remain relatively rigid upon complexation can now be successfully docked. Methods are under development to handle cases where the internal conformation of one or more of the partners changes substantially.
Protien-Ligand Docking
Protein-ligand docking is a molecular modelling technique. The goal of protein-ligand docking is to predict the position and orientation of a ligand (a small molecule) when it is bound to a protein receptor or enzyme. Pharmaceutical research employs docking techniques for a variety of purposes, most notably in the virtual screening of large databases of available chemicals in order to select likely drug candidates.
Several protein-ligand docking softwares are available, such as Autodock or EADock. There is a web service Molecular Docking Server that calculates the site, geometry and energy of small molecules interacting with proteins.
Rigid-body docking vs. flexible docking
If the bond angles, bond lengths and torsion angles of the components are not modified at any stage of complex generation, it is known as rigid body docking. A subject of speculation is whether or not rigid-body docking is sufficiently good for most docking. When substantial conformational change occurs within the components at the time of complex formation, rigid-body docking is inadequate. However, scoring all possible conformational changes is prohibitively expensive in computer time. Docking procedures which permit conformational change, or flexible docking procedures, must intelligently select small subset of possible conformational changes for consideration.
