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Molecular Docking

Molecular docking is a technique for the detection of molecular interactions for generating virtual simulations according to their molecular interactional information. It is an approach utilized in Structure Based Drug Designing (SBDD) as it predicts the ligand-protein binding and their conformation with great precision. In computer-based drug redirecting pipelines, molecular docking approaches are applicable in various ways, i.e., filtering a compound against the collection of protein structures in order to predict new drug-target interactions.

Furthermore, docking algorithms rank the ligands and predict the binding affinities by using different scoring functions. It is a frequently used approach in bioinformatics for SBDD which utilizes the structures and ligand-target interactions to predict the lead compound and to reposition the drug for medicinal use.

There are two main factors on which the conformation of the ligand-binding complex depends:

  • The possible binding positions defined by large conformational spaces.

  • Prediction of definite binding affinities associated with each conformation.

To attain minimum energy state and evaluate ligand-target conformations, a series of iterations are carried out in which different scoring functions are used.

Ligands and their importance in Molecular Docking

Ligands are the chemical compounds that interact with a biological target in such a way without disturbing its natural 3D conformation, so that the biological target protein can perform its natural function. Ligands can be synthetically made in laboratories as well as can be found naturally. To manufacture a ligand synthetically, in order to reduce the chances of errors and to save both the time and money, it’s important to design the ligand molecule first by computational means using various bioinformatics tools and databases.

The ligand preparation has a prominent effect on the docking results because the ligand recognition by any biomolecule depends on 3-dimensional orientation and electrostatic interaction, which suggests that the conformation of both the ligand as well as ligand preparation is important.

Types of Docking

On the basis of conformational changes in the structures of the ligand and target caused by the ligand-target interaction, molecular docking can be classified into following types:

1. Rigid Docking - a docking process carried out by keeping both the target and the ligand static.

2. Flexible Docking - both the target and ligand molecules are kept flexible.

3. Flexible ligand and rigid target docking - the target molecule is kept rigid while the ligand is kept flexible.

4. Ensemble Docking - utilizes various structures of rigid proteins to dock against a ligand and results are generated as a combination according to the method of selection.

5. Hybrid method - utilizes the flexible receptor and uses different methods of docking.

Importance of Molecular Docking

Molecular docking is one of the most frequently used methods in structure-based drug design, due to its ability to predict the binding-conformation of small-molecule ligands to the appropriate target binding site.

  • Drug designing is a long and tiresome task which usually takes decades to design a simple drug. This reduces the time for the novel drug discovery.

  • Moreover, it is a cost-effective process, the traditional methods require billions of dollars to create functional drugs.

Methods of Molecular Docking

Molecular docking can demonstrate the feasibility of any biochemical reaction as it is carried out before the experimental part of any investigation. There are some areas, where molecular docking has revolutionized the findings.

Following are the methods for performing molecular docking:

1. Protein-Protein Docking - involves the prediction of binding between two protein structures so as to form a protein complex using features such as steric and physicochemical complementarity at the protein-protein interface. This involves the prediction of conformational changes between unbound and bound structures. This is possible using structural data with a deeper understanding of the fundamental principles of protein interactions together with available advanced computational capabilities.

2. Protein-Ligand Docking - can be further classified into three types that are based on the structure of the Protein and Ligand:

2.1. Rigid ligand and rigid receptor docking:

When the ligand and receptor are both treated as rigid bodies, the search space is very limited, considering only three translational and three rotational degrees of freedom. In this case, ligand flexibility could be addressed by using a pre-computed set of ligand conformations, or by allowing for a degree of atom-atom overlap between the protein and ligand.

2.2. Flexible ligand and rigid receptor docking:

For systems whose behavior follows the induced fit paradigm it is of vital importance to consider the flexibilities of both the ligand and receptor since in that case both the ligand and receptor change their conformations to form a minimum energy perfect-fit complex.

2.3. Flexible ligand and flexible receptor docking:

The intrinsic mobility of proteins has been proved to be closely related to ligand binding behavior and it has been reviewed by Teague. Incorporating receptor flexibility is a significant challenge in the field of docking. Ideally, using MD simulations could model all the degrees of freedom in the ligand-receptor complex.

3. Protein-Peptide Docking - the interest in peptide therapeutics triggered the rapid development of new techniques dedicated to protein-peptide docking which are being increasingly incorporated into the drug discovery and design process.

Protein–peptide docking methods can be divided into three categories:

  • Template-based docking

  • Local docking

  • Global docking

4. Protein-Nucleic Acid Docking - Proteins interact with DNA and RNA through similar physical forces, which include electrostatic interactions (salt bridges), dipolar interactions (hydrogen bonding, H-bonds), entropic effects (hydrophobic interactions), and dispersion forces (base stacking). These forces contribute in varying degrees to proteins binding in a sequence-specific (tight) or non-sequence-specific (loose) manner.

Fundamentals of Docking

The aim of molecular docking is to give a prediction of the ligand-receptor complex structure using computation methods. Docking can be achieved through two interrelated steps: first by sampling conformations of the ligand in the active site of the protein; then ranking these conformations via a scoring function.

Ideally, sampling algorithms should be able to reproduce the experimental binding mode and the scoring function should also rank it highest among all generated conformations.

Tools for Molecular Docking

There is a huge number of web-based and stand-alone tools available for molecular docking analysis both commercial and non-commercial. These include:

  • AutoDock Vina

  • Molecular Operating Environment (MOE)


  • SwissDock

  • CABSDock

  • MDock

  • PatchDock

  • ClusPro

  • Discovery Studio+

Bioinfolytics & Our Services

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Predicting a protein-ligand complex can really be nerve-wracking. Through BioinfoLytics, We can gladly help you with molecular docking. Our skillful and experienced bioinformaticians can provide you services for protein-small molecule (ligand) docking, protein-nucleic acid docking, and protein-protein docking.

If you’re a Bioinformatician and have such skills for performing and analyzing molecular docking for computational drug designing purposes using various bioinformatics tools and databases, we’ll be glad to provide you our platform of BioinfoLytics, where you can sell your skills as a freelancer.

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