What is Molecular Docking? Purpose, Types and softwares used in Molecular Docking.

Author: Atharva Tilewale

What is Molecular Docking?

• Molecular docking is a computational technique used in drug discovery and biological processes to determine the preferred orientation of a small molecule (ligand) when bound to a target protein (receptor). The goal of molecular docking is to determine the optimal binding of the ligand at the receptor binding site, thus predicting the strength and nature of the ligand-receptor interaction. 
• Imagine you have a race that consists of two parts that fit together perfectly, like a car and its driver. In the scientific world, there are little things called molecules. Some molecules are like puzzle pieces that fit perfectly into certain pieces of other molecules, just like a car puzzle fits into the driver’s puzzle. 
• Molecular docking is something like this, scientists use computers to understand how different molecules fit together as if you were trying to put together a puzzle. They study the shape of molecules and how they stick together; like examining the shape of a puzzle and determining how they fit together.

So, when scientists perform molecular docking, they are attempting to determine how different molecules might stick together and how strong their bond might be. This allows them to better understand how medicines work in our bodies and how to develop better medicines to help people feel better.

In recent years, molecular docking has became a crucial component for in-silico drug development. This method tells about the atomic-level interactions between a small molecule and a protein. This makes it possible for scientists to investigate how tiny compounds, like nutraceuticals, behave within a target protein’s binding site and carry out the basic biochemical mechanism underlying this interaction. The method is structure-based and needs a high-resolution 3D image of the target protein, which can be obtained using methods such as cryo-electron microscopy, nuclear magnetic resonance spectroscopy, or X-ray crystallography.

What is the Purpose Molecular Docking?

The purpose of molecular docking is to help scientists understand how molecules interact with each other. By determining how different molecules fit together and the strength of their bonds, scientists can:

• Discover new drugs: Molecular docking is a process used in drug discovery to identify molecules that can become new drugs. Scientists can identify potential drug candidates by predicting how molecules bind to specific targets in the body. 
• Improving existing medicine: This could lead to better treatment with fewer side effects. 
• Understanding the Biological Processes: By studying their interactions, researchers can learn more about the development and treatment of the disease. 
• Material Designing: It can also be used to create new materials with special properties, such as catalysts for chemical reactions or sensors to detect environmental molecules. 

Types Of Molecular Docking

Rigid docking, flexible-rigid docking and flexible docking are three types of docking operations (depending on the flexibility of interacting molecules, receptors and ligands). Flexibility becomes more efficient and reliable because molecules can have different relative positions and bond lengths. Researchers examined various molecular docking algorithms based on rigid and flexible docking. 

1. Rigid Docking:

Each molecule maintains its geometry because its shape does not change. Due to their simplicity, only translational and rotational degrees of freedom are considered for docking. Early docking methods, which were available for large molecules such as two protein molecules, are not used in modern docking studies due to poor quality and lack of reliability. With this method, the lock-key principle can be used. 

2. Flexible-Rigid Docking: 

In this case, either the ligand or receptor is considered to be a rigid molecule. In general, the shape of the receptor remains unchanged while the structure of the ligand changes. This method is widely used because it is more efficient and reliable than the rigid placement method.

3. Flexible (Soft) Docking:

A completely flexible docking method that treats the ligand and receptor as physically flexible. The rotation of molecules (ligands and receptors) is calculated to find the apparent alignment and orientation of molecules interacting with each other. The torsion angle and rotatable bonds can be adjusted to change the shape of the molecule. This approach leads to extremely precise docking conformations to match experimental data, but it requires a long time and a lot of money.

Induced conformation methods can be used in semi-flexible and fully flexible docking methods, and the docking process will be complex when the interacting molecules have many conformational degrees of freedom.

Docking Softwares List

1. Dock: It was developed by the UCSF Chimera team. Dock is an user-friendly software for docking of small molecules into receptor’s binding sites. It uses grid-based techniques and scoring functions to evaluate ligand-receptor binding affinity. It supports input file formats such as PDB, MOL2, and SDF. It can be accessed from http://dock.compbio.ucsf.edu/.
2. Autodock: It was created by The Scripps Research Institute. Autodock is an open-source program for docking in both rigid and flexible modes. It optimizes ligand placement using a genetic algorithm and offers multiple scoring functions. It supports input file formats such as PDB, MOL2, and SDF. You can download Autodock from http://autodock.scripps.edu.
3. Argus Lab 4.0.1: It was developed by Mark Thomson at Pacific Northwest National Laboratory. Argus Lab models solvent effects and combines classical and quantum mechanics algorithms. It is used for tasks like graphic creation, drug design, and molecule modelling. Visit http://www.arguslab.com for Argus Lab.
4. GOLD™: This is a protein-ligand docking software that features user-defined scoring functions and various docking options. It supports virtual screening and high-throughput screening analysis. GOLD is available at http://www.ccdc.cam.ac.uk/products/lifesciences/gold.
5. MolDock: MolDock was developed by MolSoft LLC. It quickly and effectively docks small compounds into receptor binding sites using the FFT technique. It offers scoring based on the van-der-waals forces, electrostatic interactions, and ligand-receptor complementarity. Find MolDock at https://www.molsoft.com/about.html.
6. Discovery Studios: It was developed by Dassault Systèmes BIOVIA. Discovery Studio is a suite for molecular modelling and simulation. It includes tools for protein modelling, virtual screening, molecular docking, and dynamics analysis. It supports various docking algorithms and provides visualization and analysis tools. It shows hydrophilic and hydrophobic bonds within the receptor and ligand molecules. 2D interaction can also be seen between active site residues and ligand molecule. Access Discovery Studio at https://discover.3ds.com/discovery-studio-visualizer-download.
7. Chimera: Chimera was created by the University of California, San Francisco. It  allows users to visualize and simulate molecular structures. Its “Dock Prep” component prepares proteins and ligands for docking simulations, and it offers tools for result analysis. Find Chimera at https://www.cgl.ucsf.edu/chimera/

Applications of Molecular Docking

1. Lead Identification/Virtual Screening: Molecular docking predicts the binding affinity of small compounds to a target protein, which helps in the identification of potential therapeutic treatments from large compound libraries.
2. Lead Optimization: After identifying lead compounds, docking helps to refine their structure to increase binding affinity and selectivity, and can be used to design novel analogues.
3. Bioremediation: Docking predicts the binding affinity of small molecules of the enzymes that are involved in environmental contaminant breakdown, facilitating the design of enzyme inhibitors or activators for bioremediation.
4. Structure Elucidation: Docking helps clarify the structures of proteins with unclear structures by predicting how small molecules bind to them. This information can help in the creation of homology models of proteins based on the predicted binding mode and experimental data refinement.
5. Molecular Dynamics Simulation: Docking and molecular dynamics simulations combined allow the examination of protein-ligand complex dynamics, including conformational changes and complex stability, providing insights into protein-ligand interactions over time.
6. ADMET Prediction: Docking software like AutoDock Vina, GOLD, Glide, and Schrödinger Suite predict the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of small compounds, aiding in early drug development by filtering out molecules with undesirable qualities.

Challenges of Molecular Docking

Docking methods have many limitations and problems. Docking results that match the results of the experimental procedure may not be accurate.

1. In silico simulation of the identification of various molecular features that lead to interactions can be complex, difficult and time-consuming. Each stage of the deployment process is designed to create a more complex environment.
2. When dealing with low resolution crystal structure data for molecules and compounds with unknown data, it will be more difficult to determine the exact binding site of the receptor. 
3. Most docking methods do not necessarily allow for hydrated docking, and it is difficult to predict when water molecules will participate in macromolecule-ligand interactions. Docking algorithms are often used to remove water molecules from the binding envelope of the receptor before docking. For example, the occupancy of a receptor is not always accurate when a water molecule is tightly bound or functionally active at the binding site. In these cases, hydrated placement is essential. 
4. Determining the force field and some other necessary factors during the placement process is not a difficult process. 
5. The majority of docking software programs only accept biomolecules as receptors, which include proteins, enzymes, DNA, RNA, and so forth. However, they do not identify synthetic-organic, synthetic-organic–inorganic hybrid, or inorganic compounds as receptors other than biomolecules.
6. A few docking technologies additionally support ions. The program immediately neutralises the charges when they are interpreted as ligands. Thus, the user needs to thoroughly review the charges manually.

References

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