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Protein- Ligand Interaction


Objective :


To find the interaction between the protein and a ligand molecule 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 which receives signals and can be defined as a molecule which recognizes a small molecule, which on binding triggers 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 binds to a multiple receptor sites.


Drug receptors usually remain without endogenous ligand. The receptors for these drugs molecules can be an enzyme, an ion channels, proteins, 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 to 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.


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 design 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 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 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 by 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 deigning. There are so many computational tools available for building a molecule.


After modeling a molecule, check where the ligand get docked onto the receptor, and check whether the ligand fits for the target molecule and go for Docking studies.


Protein ligand interaction:


Proteins are the fundamental units of all living cells and plays a vital role in various cellular functions. Each protein has specific function in our body. For example hemoglobin is a protein found in Red Blood Cells that carries oxygen from lungs to cells and collects the carbon dioxide back to the lungs. The structure of the protein determines its function. The binding of a protein with other molecules is very specific to carry out its function properly. For this reason every protein has a particular structure. A molecule is a small chemical element that is made up of two or more atoms held together by chemical bonds. A drug is a small molecule that can interact, bind and control the function of biological receptors that helps to cure a disease .


Protein–ligand interactions are essential for all processes happening in living organisms. Ligand-mediated signal transmission through molecular complementary is essential to all life processes; these chemical interactions comprises biological recognition at molecular level. The evolution of the protein functions depends on the development of specific sites which are designed to bind ligand molecules. Ligand binding capacity is important for the regulation of biological functions. Protein-Ligand interactions occur through the molecular mechanics involving the conformational changes among low affinity and high affinity states. Ligand binding interactions changes the protein state and protein function.


Key concepts of protein ligand interaction :


  • Every biological reaction is initiated by protein-ligand interaction step. Such reactions never involve in the binding of single ligand or single step.


  • Binding of two or more ligands to a same protein indicates mutual interaction.


  • Ligand binding plays an important role in regulation of biological function.


  • Ligand binding may leads to the conformational changes in proteins.


  • Ligand and macromolecule interaction provides the strength of the interaction.


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 as “lock and key” model. Here the protein can be called as a lock and the ligand can be called as key, which describes the best fit orientation of the ligand which it goes and binds to a particular protein. To perform a docking, first one may require a protein molecule. The protein structures and ligands are the inputs for the docking.



Figure1: Example of Docking 




Docking can be based on two separate platforms.


1. Search algorithm


Search algorithm creates an optimum number of configurations that includes the binding modes which are determined experimentally. Configurations are evaluated using scoring functions to differentiate the binding modes from the other modes.


The common search algorithms are:


  • Monte Carlo methods
  • Genetic algorithms
  • Fragment-based methods
  • Point complimentary methods
  • Tabu searches
  • Systematic searches
  • Molecular dynamics.


2. Scoring function:


Scoring functions are developed to find the interactions between the protein- protein interactions and protein-DNA interactions. Scoring methods are the mathematical methods used to predict the strength of interaction between two molecules.


Steps for Docking :


  • Preparation of the Protein molecule :

Download the protein structure to the working directory. Remove the water molecules and add hydrogens to the molecule to satisfy the valances of the molecule. X-ray crystallographic structures cannot resolove the hydrogen, so in most of the PDB structures hydrogens are absent. Remove the disulphide and trisulphide bonds of a protein using AutoDock. After the preparation of the molecules, molecules has to be minimized.


  • Preparation of ligand molecules :

Prepare a ligand molecule which is going to bind to the target add hydrogen atoms to the molecule and filter the unwanted molecules based on their properties like water and small ions. If the stereoisomers are missing from the Molecule it requires adding stereo chemical information. Optimize the geometry of the molecule. Take the molecule for docking studies.


  • Surface representation:

Take a receptor and ligand molecule for studies, receptor as a static and ligand molecule as flexible. Find the Surface of the molecules by using geometric features of the molecules. Grid points are used to find the surface area.


  • Feature calculation

Features are the methods which are used to find the potential docking sites that are derived from surface representation.


  • Docking

It is important to find the cavities on the surface of the receptor in protein Ligand interaction.


  • Evaluation of Docking result:

Dock the each individual parts, docking of each segments gives the total score.



Types of Docking: 

Rigid Docking: In a rigid molecular docking the molecules are referred as rigid objects they cannot change their shape during the docking


Flexible Docking: In a flexible docking the molecules are referred as flexible objects that they can change their shapes according to the ligand and the 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.


  • X-ray crystallography


  • Lead optimization


  • Combinatorial library design


  • Protein-Protein docking.


  • Chemical mechanism studies.


Home page of AutoDock :



FIgure2: GUI of AutoDock









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