Protein-Ligand Docking

Ligands are the chemical compounds that interact with a biological target without disturbing its natural 3D conformation. Protein–ligand docking predicts the position and orientation of a ligand (a small molecule) when it is bound to a protein receptor or enzyme. Protein-ligand interactions are fundamental to many biological processes. The functions of a protein can be regulated by binding to ligands. A protein can have conformational changes under physiological conditions, which in turn are responsible for the conformational transitions among low- and high-affinity states for the ligands. Ligand binding can stabilize the protein in some specific states and thereby switch the protein among states of different functions.

Types of Protein-Ligand Docking

The mutual adaptation of a ligand with its receptor is crucial to understanding ligand binding and protein function. One of the major challenges in molecular docking is how to account for this adaptation in docking calculations.

The docking problem can be divided into following categories:

1. Rigid Body Docking: Rigid body docking ignores the flexibility of the molecules and treats them like rigid objects. It explores only six degrees of translational and rotational freedom, hence excluding any kind of flexibility.
2. Rigid Receptor – Flexible Ligand Docking: In this type of docking only the ligand is treated as flexible, the receptor is rigid. Thus it considers only the conformational space of the ligand.
3. Flexible Receptor – Flexible Ligand Docking: In this type of docking both protein and ligand are treated as flexible. Flexible receptor and flexible ligand interactions help in mimicking the binding process in real life.

4. Blind Docking: Blind Docking refers to docking a ligand to the whole surface of a protein without any prior knowledge of the target pocket. Blind docking involves several trials/runs and several energy calculations before a favorable protein-ligand complex pose is found. However, the number of trials and energy evaluations necessary for a blind docking job is unknown. 

Protein-Peptide Docking

A peptide is a short chain of amino acids. The amino acids in a peptide are connected to one another in a sequence by bonds called peptide bonds. Typically, peptides are distinguished from proteins by their shorter length, although the cut-off number of amino acids for defining a peptide and protein can be arbitrary. Peptides have recently attracted much attention as promising drug candidates. Rational design of peptide-derived therapeutics require structural characterization of the underlying protein-peptide interaction. Reliable computational tools are used for experimental characterization. In protein-peptide docking, first we predict the structure of the protein-peptide complex, starting from the protein structure and the peptide sequence, including variable degrees of information about the peptide binding site and/or conformation.

Tools and Servers Available for Molecular Docking

AutoDock Vina, SwissDock, rDock, LZerD, PatchDock, ZDock VirtualFlow, MOE (Molecular Operating Environment), HADDOCK and many others.

AutoDock Vina

AutoDock Vina is a successor of AutoDock, significantly improved in terms of accuracy and performance. AutoDock is a molecular modeling simulation software. It is especially effective for protein-ligand docking. AutoDock Vina was found to be a strong competitor against the other docking programs. It significantly improved the average accuracy of the binding mode predictions compared to AutoDock. AutoDock Vina is one of the most cited docking software applications in the research community.

SwissDock

SwissDock is a web service that predicts the molecular interactions that may occur between a target protein and a small molecule. It is used to propose a binding mode for a ligand, create figures for your articles, generate a complex to perform subsequent calculations and design inhibitors for the target of your choice.

MOE

Molecular Operating Environment (MOE) is a drug discovery software platform that integrates visualization, modeling and simulations, as well as methodology development, in one package. MOE scientific applications are used by biologists, medicinal chemists and computational chemists in pharmaceutical, biotechnology and academic research.

PatchDock

The PatchDock server performs structure prediction of protein–protein and protein–small molecule complexes. PatchDock is a geometry-based molecular docking algorithm. It is aimed at finding docking transformations that yield good molecular shape complementarity.

rDock

rDock, previously known as RiboDock, is an open-source molecular docking software that can be used for docking small molecules against proteins and nucleic acids. It is primarily designed for high-throughput virtual screening and prediction of binding mode.

VirtualFlow

VirtualFlow is able to use a variety of the most powerful docking programs. VirtualFlow can access vast regions of the chemical space and identify molecules that bind with high affinity to target proteins.

HADDOCK

HADDOCK is a tool that distinguishes itself from ab-initio docking methods in the fact that it encodes information from identified or predicted protein interfaces in ambiguous interaction restraints (AIRs) to drive the docking process. It is an integrative platform for the modeling of biomolecular complexes. It supports a large variety of input data and can deal with multi-component assemblies of proteins, peptides, small molecules and nucleic acids.