To find the interaction between drug molecule and receptor by performing docking studies.
A molecule is a small chemical element that is made up of two or more atoms held together by chemical bonds. A molecule can be composed of either single kind of element (e.g. H2) or different kinds of elements (e.g. CO2). Molecules can be found in both living things and non living things. A drug is a small molecule that can interact, bind and control the function of biological receptors that helps to cure a disease. Receptors are proteins that interact with other biological molecules to maintain various cellular functions in body. Enzymes, hormone receptors, cell signaling receptors, neurotransmitter receptors etc. are some important receptors in our body.
Drug designing is a process of designing a drug molecule that can interact and bind to a target. Receptors are molecules which can be seen on the surface of the cell transmits signals upon binding by a small molecule triggering a cellular process. In an unbounded state receptor, functionalities of the receptor remain silent. Hence this definition says that receptor binds specifically to a particular ligand or vice versa, but in some cases high concentrations of ligands will bind to multiple receptor sites.
Drug receptors usually remain without endogenous ligand. The receptors for these drugs molecules can be enzyme, ion channel, protein, nucleic acids etc. Hence the drug molecule will go and cross link the DNA and stops DNA replication. It is used to treat malignant tumors. Receptors for endogenous regulatory ligands are hormones, neurotransmitters, autacoids, growth factors, cytokines etc. Hence the function of these receptors is to sense the ligands and initiate the response. For example, Aspirin is a small pain killer drug molecule which contains nine carbon atoms, eight hydrogen atoms and four oxygen atoms. Design of the molecules should be complementary in shape and charge to the target.
Drug molecule mediates signal transmission through a molecule that is complementary which is essential for a biological process. The evolution of the receptor functions depends on the development of specific sites which are designed to bind drug molecules. Drug molecule binding capacity is important for the regulation of biological functions. Drug-receptor interactions occur through the molecular mechanics involving the conformational changes among low affinity and high affinity states. Drug molecule binding interactions changes the receptor state and receptor function.
Molecular modeling includes computational techniques that are used to model a molecule. Drug designing by using these modeling techniques is referred to as computer-aided drug design. Computer based drug designing is a fast, automatic, very low cost process. It can be done either by Ligand based drug design or structure based drug design. Ligand based drug design is purely based on the model which is going to bind to the target. Defining of pharmacophoric regions are necessary for the molecule inorder to bind to the target but structure based drug design is based on the 3 dimensional structure of the target. If any target is not available, it can be created using homology modeling. Using the structure of the target, predict the drug molecules binding affinity to the target. Building a molecule using computer techniques is a very important step in drug designing. There are so many computational tools available for building a molecule.
After modeling a molecule, check where the ligand gets docked onto the receptor and check whether the ligand fits for the target molecule and then go for docking studies.
What is Docking?
Docking is a method which predicts the preferred orientation of one molecule to another molecule when they are bound together to form a stable complex. Molecular docking can be referred to as “lock and key” model. Here the protein can be called as lock and the ligand can be called as key. It describes the best fit orientation of the ligand required for binding to a particular protein. To perform a docking, first one may require a protein molecule. The protein structure and ligands are the inputs for docking.
Figure1: Example of Docking
Docking can be based on two separate platforms.
Search algorithm creates an optimum number of configurations that includes binding modes which are determined experimentally. Configurations are evaluated using scoring functions to differentiate the binding modes from other modes.
The common search algorithms are:
- Point complimentary methods
Scoring functions are developed to find the interactions between protein-protein interactions and protein-DNA interactions. Scoring methods are mathematical methods used to predict the strength of interaction between two molecules.
Steps for Docking :
Take receptor and ligand molecules for studies. Receptor molecule as static and ligand molecule as flexible.
Dock the ligand molecule into a biding pocket in the receptor. Generate the large number of possible orientations.
Evaluate the model/Docking result based on the energy.
Types of Docking:
Rigid Docking: In a rigid molecular docking, the molecules are referred toas rigid objects which cannot change their shape during the docking.
Flexible Docking: In a flexible docking, where molecules are referred to as flexible objects and they can change their shapes according to the ligand and target during docking process.
AutoDock is a docking tool, which is designed to predict the behavior of the small molecules and helps user to perform the docking of ligands to a set of grids which describes the target, once docking completes result can visualize in 3d view. AutoDock 4 is freely available under the GNU General Public License. AutoDock uses a Monte Carlo simulation with a rapid energy evaluation using grid based molecular affinity potentials. It is given a volume around the protein, the rotatable bonds for the substrate, and an arbitrary starting configuration, and the procedure produces a relatively unbiased docking.
Different applications of AutoDock:
- Structure based drug design.
- Combinatorial library design
- Chemical mechanism studies.
Home page of AutoDock:
Figure 2: GUI of AutoDock
This experiment is in the process of re-edit