Docking (molecular)

Docking glossary
Receptor or host or lock The "receiving" molecule, most commonly a protein or other biopolymer. Ligand or guest or key The complementary partner molecule which binds to the receptor. Ligands are most often small molecules but could also be another biopolymer. Docking Computational simulation of a candidate ligand binding to a receptor. Binding mode The orientation of the ligand relative to the receptor as well as the conformation of the ligand and receptor when bound to each other. Pose A candidate binding mode. Scoring The process of evaluating a particular pose by counting the number of favorable intermolecular interactions such as hydrogen bonds and hydrophobic contacts. Ranking The process of classifying which ligands are most likely to interact favorably to a particular receptor based on the predicted free-energy of binding. Docking assessment (DA) Procedure to quantify the predictive capability of a docking protocol.

In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using, for example, scoring functions.

File:Docking representation 2.png

Schematic illustration of docking a small molecule ligand (green) to a protein target (black) producing a stable complex.

File:Docking GPCR example.webm

Docking of a small molecule (green) into the crystal structure (PDB: 3SN6) of the beta-2 adrenergic G-protein coupled receptor.

The associations between biologically relevant molecules such as proteins, nucleic acids, carbohydrates, and lipids play a central role in signal transduction. Furthermore, the relative orientation of the two interacting partners may affect the type of signal produced (e.g., agonism vs antagonism). Therefore, docking is useful for predicting both the strength and type of signal produced.

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. Characterisation of the binding behaviour plays an important role in rational design of drugs as well as to elucidate fundamental biochemical processes.

Definition of problem

One can think of molecular docking as a problem of “lock-and-key”, in which one wants to find the correct relative orientation of the “key” which will open up the “lock” (where on the surface of the lock is the key hole, which direction to turn the key after it is inserted, etc.). Here, the protein can be thought of as the “lock” and the ligand can be thought of as a “key”. Molecular docking may be defined as an optimization problem, which would describe the “best-fit” orientation of a ligand that binds to a particular protein of interest. However, since both the ligand and the protein are flexible, a “hand-in-glove” analogy is more appropriate than “lock-and-key”. During the course of the docking process, the ligand and the protein adjust their conformation to achieve an overall "best-fit" and this kind of conformational adjustment resulting in the overall binding is referred to as "induced-fit".

Molecular docking research focusses on computationally simulating the molecular recognition process. It aims to achieve an optimized conformation for both the protein and ligand and relative orientation between protein and ligand such that the free energy of the overall system is minimized.

Docking approaches

Two approaches are particularly popular within the molecular docking community. One approach uses a matching technique that describes the protein and the ligand as complementary surfaces. The second approach simulates the actual docking process in which the ligand-protein pairwise interaction energies are calculated. Both approaches have significant advantages as well as some limitations. These are outlined below.

Shape complementarity

Geometric matching/ shape complementarity methods describe the protein and ligand as a set of features that make them dockable. These features may include molecular surface / complementary surface descriptors. In this case, the receptor’s molecular surface is described in terms of its solvent-accessible surface area and the ligand’s molecular surface is described in terms of its matching surface description. The complementarity between the two surfaces amounts to the shape matching description that may help finding the complementary pose of docking the target and the ligand molecules. Another approach is to describe the hydrophobic features of the protein using turns in the main-chain atoms. Yet another approach is to use a Fourier shape descriptor technique. Whereas the shape complementarity based approaches are typically fast and robust, they cannot usually model the movements or dynamic changes in the ligand/ protein conformations accurately, although recent developments allow these methods to investigate ligand flexibility. Shape complementarity methods can quickly scan through several thousand ligands in a matter of seconds and actually figure out whether they can bind at the protein’s active site, and are usually scalable to even protein-protein interactions. They are also much more amenable to pharmacophore based approaches, since they use geometric descriptions of the ligands to find optimal binding.

Simulation

Simulating the docking process as such is much more complicated. In this approach, the protein and the ligand are separated by some physical distance, and the ligand finds its position into the protein’s active site after a certain number of “moves” in its conformational space. The moves incorporate rigid body transformations such as translations and rotations, as well as internal changes to the ligand’s structure including torsion angle rotations. Each of these moves in the conformation space of the ligand induces a total energetic cost of the system. Hence, the system's total energy is calculated after every move.

The obvious advantage of docking simulation is that ligand flexibility is easily incorporated, whereas shape complementarity techniques must use ingenious methods to incorporate flexibility in ligands. Also, it more accurately models reality, whereas shape complimentary techniques are more of an abstraction.

Clearly, simulation is computationally expensive, having to explore a large energy landscape. Grid-based techniques, optimization methods, and increased computer speed have made docking simulation more realistic.

Mechanics of docking

File:Overview docking.png

Docking flow-chart overview

To perform a docking screen, the first requirement is a structure of the protein of interest. Usually the structure has been determined using a biophysical technique such as x-ray crystallography or NMR spectroscopy, but can also derive from homology modeling construction. This protein structure and a database of potential ligands serve as inputs to a docking program. The success of a docking program depends on two components: the search algorithm and the scoring function.

Search algorithm

Main article: Searching the conformational space for docking

The search space in theory consists of all possible orientations and conformations of the protein paired with the ligand. However, in practice with current computational resources, it is impossible to exhaustively explore the search space—this would involve enumerating all possible distortions of each molecule (molecules are dynamic and exist in an ensemble of conformational states) and all possible rotational and translational orientations of the ligand relative to the protein at a given level of granularity. Most docking programs in use account for the whole conformational space of the ligand (flexible ligand), and several attempt to model a flexible protein receptor. Each "snapshot" of the pair is referred to as a pose.

A variety of conformational search strategies have been applied to the ligand and to the receptor. These include:

• systematic or stochastic torsional searches about rotatable bonds
• molecular dynamics simulations
• genetic algorithms to "evolve" new low energy conformations and where the score of each pose acts as the fitness function used to select individuals for the next iteration.

Ligand flexibility

Conformations of the ligand may be generated in the absence of the receptor and subsequently docked or conformations may be generated on-the-fly in the presence of the receptor binding cavity, or with full rotational flexibility of every dihedral angle using fragment based docking. Force field energy evaluation are most often used to select energetically reasonable conformations, but knowledge-based methods have also been used.

Receptor flexibility

Computational capacity has increased dramatically over the last decade making possible the use of more sophisticated and computationally intensive methods in computer-assisted drug design. However, dealing with receptor flexibility in docking methodologies is still a thorny issue. The main reason behind this difficulty is the large number of degrees of freedom that have to be considered in this kind of calculations. Neglecting it, however, leads to poor docking results in terms of binding pose prediction.

Multiple static structures experimentally determined for the same protein in different conformations are often used to emulate receptor flexibility. Alternatively rotamer libraries of amino acid side chains that surround the binding cavity may be searched to generate alternate but energetically reasonable protein conformations.

Scoring function

Main article: Scoring functions for docking

Docking programs generate a large number of potential ligand poses, of which some can be immediately rejected due to clashes with the protein. The remainder are evaluated using some scoring function, which takes a pose as input and returns a number indicating the likelihood that the pose represents a favorable binding interaction and ranks one ligand relative to another.

Most scoring functions are physics-based molecular mechanics force fields that estimate the energy of the pose within the binding site. The various contributions to binding can be written as an additive equation:

$\bigtriangleup G_{bind} = \bigtriangleup G_{solvent} + \bigtriangleup G_{conf} + \bigtriangleup G_{int} + \bigtriangleup G_{rot} + \bigtriangleup G_{t/t} + \bigtriangleup G_{vib}$

The components consist of solvent effects, conformational changes in the protein and ligand, free energy due to protein-ligand interactions, internal rotations, association energy of ligand and receptor to form a single complex and free energy due to changes in vibrational modes. A low (negative) energy indicates a stable system and thus a likely binding interaction.

An alternative approach is to derive a knowledge-based statistical potential for interactions from a large database of protein-ligand complexes, such as the Protein Data Bank, and evaluate the fit of the pose according to this inferred potential.

There are a large number of structures from X-ray crystallography for complexes between proteins and high affinity ligands, but comparatively fewer for low affinity ligands as the later complexes tend to be less stable and therefore more difficult to crystallize. Scoring functions trained with this data can dock high affinity ligands correctly, but they will also give plausible docked conformations for ligands that do not bind. This gives a large number of false positive hits, i.e., ligands predicted to bind to the protein that actually don't when placed together in a test tube.

One way to reduce the number of false positives is to recalculate the energy of the top scoring poses using (potentially) more accurate but computationally more intensive techniques such as Generalized Born or Poisson-Boltzmann methods.

Docking assessment

The interdependence between sampling and scoring function affects the docking capability in predict plausible poses or binding affinities for novel compounds. Thus, an assessment of a docking protocol is generally required (when experimental data is available) to determine its predictive capability. Docking assessment can be performed using different strategies, such as:

• docking accuracy (DA) calculation;
• the correlation between a docking score and the experimental response or determination of the enrichment factor (EF);
• the distance between an ion-binding moiety and the ion in the active site;
• the presence of induce-fit models.

Docking accuracy

Docking accuracy represents one measure to quantify the fitness of a docking program by rationalizing the ability to predict the right pose of a ligand with respect to that experimentally observed.

Enrichment factor

Docking screens can be also evaluated by the enrichment of annotated ligands of known binders from among a large database of presumed non-binding, “decoy” molecules. In this way, the success of a docking screen is evaluated by its capacity to enrich the small number of known active compounds in the top ranks of a screen from among a much greater number of decoy molecules in the database. The area under the receiver operating characteristic (ROC) curve is widely used to evaluate its performance.

Prospective

Resulting hits from docking screens are subjected to pharmacological validation (e.g. IC_50, affinity or potency measurements). Only prospective studies constitute conclusive proof of the suitability of a technique for a particular target.

Benchmarking

The potential of docking programs to reproduce binding modes as determined by X-ray crystallography can be assed by a range of docking benchmark sets.

For small molecules, several benchmark data sets for docking and virtual screening exist e.g. Astex Diverse Set consisting of high quality protein−ligand X-ray crystal structures or the Directory of Useful Decoys (DUD) for evaluation of virtual screening performance.

An evaluation of docking programs for their potential to reproduce peptide binding modes can be assessed by Lessons for Efficiency Assessment of Docking and Scoring (LEADS-PEP).

Applications

A binding interaction between a small molecule ligand and an enzyme protein may result in activation or inhibition of the enzyme. If the protein is a receptor, ligand binding may result in agonism or antagonism. Docking is most commonly used in the field of drug design — most drugs are small organic molecules, and docking may be applied to:

• hit identification – docking combined with a scoring function can be used to quickly screen large databases of potential drugs in silico to identify molecules that are likely to bind to protein target of interest (see virtual screening).
• lead optimization – docking can be used to predict in where and in which relative orientation a ligand binds to a protein (also referred to as the binding mode or pose). This information may in turn be used to design more potent and selective analogs.
• Bioremediation – Protein ligand docking can also be used to predict pollutants that can be degraded by enzymes.

List of protein-ligand docking software

The number of docking programs currently available is high and has been steadily increasing over the last decades. The following list presents an overview of the most common protein-ligand docking programs, listed alphabetically, with indication of the corresponding year of publication, involved organisation or institution, short description, availability of a webservice and the license. This table is comprehensive but not complete.

Program	Year Published	Organisation	Description	Webservice	License
1-Click Docking	2011	Mcule	Docking predicts the binding orientation and affinity of a ligand to a target	Available →	Basic free version
AADS	2011	Indian Institute of Technology	Automated active site detection, docking, and scoring(AADS) protocol for proteins with known structures based on Monte Carlo Method	Available →	Free to use Webservice
ADAM	1994	IMMD Inc.	Prediction of stable binding mode of flexible ligand molecule to target macromolecule	No	Commercial
AutoDock	1990	The Scripps Research Institute	Automated docking of ligand to macromolecule by Lamarckian Genetic Algorithm and Empirical Free Energy Scoring Function	No	Freeware →
AutoDock Vina	2010	The Scripps Research Institute	New generation of AutoDock	No	Open source →
BetaDock	2011	Hanyang University	Based on Voronoi Diagram	No	Freeware →
Blaster	2009	University of California San Francisco	Combines ZINC databases with DOCK to find ligand for target protein	Available →	Freeware
BSP-SLIM	2012	University of Michigan	A new method for ligand-protein blind docking using low-resolution protein structures	Available →	Freeware
DARWIN	2000	The Wistar Institute	Prediction of the interaction between a protein and another biological molecule by genetic algorithm	No	Freeware
DIVALI	1995	University of California-San Francisco	Based on AMBER-type potential function and genetic algorithm	No	Freeware
DOCK	1988	University of California-San Francisco	Based on Geometric Matching Algorithm	No	Freeware for academic use →
DockingServer	2009	Virtua Drug Ltd	Integrates a number of computational chemistry software	Available →	Commercial
DockVision	1992	DockVision	Based on Monte Carlo, genetic algorithm, and database screening docking algorithms	No	Commercial →
EADock	2007	Swiss Institute of Bioinformatics	Based on evolutionary algorithms	Available →	Freeware →
eHiTS	2006	SymBioSys Inc	Exhausted search algorithm	No	Commercial →
EUDOC	2001	Mayo Clinic Cancer Center	Program for identification of drug interaction sites in macromolecules and drug leads from chemical databases	No	Academic
FDS	2003	University of Southampton	Flexible ligand and receptor docking with a continuum solvent model and soft-core energy function	No	Academic
FlexX	2001	BioSolveIT	Incremental build based docking program	No	Commercial →
FlexAID	2015	University of Sherbrooke	Target side-chain flexibility and soft scoring function, based on surface complementarity	No	Open source →
FlexPepDock	2010	The Hebrew University	Modeling of peptide-protein complexes, implemented within the Rosetta framework	Available →	Freeware
FLIPDock	2007	Scripps Research Institute	Genetic algorithm based docking program using FlexTree data structures to represent a protein-ligand complex	No	Free for academic use →
FLOG	1994	Merck Research Laboratories	Rigid body docking program using databases of pregenerated conformations	No	Academic
FRED	2003	OpenEye Scientific	Systematic, exhaustive, nonstochastic examination of all possible poses within the protein active site combined with scoring Function	No	Free for academic use →
FTDOCK	1997	Biomolecular Modelling Laboratory	Based on Katchalski-Katzir algorithm. It discretises the two molecules onto orthogonal grids and performs a global scan of translational and rotational space	No	Freeware →
GEMDOCK	2004	National Chiao Tung University	Generic Evolutionary Method for molecular docking	No	Freeware →
Glide	2004	Schrödinger	Exhaustive search based docking program	No	Commercial →
GOLD	1995	Collaboration between the University of Sheffield, GlaxoSmithKline plc and CCDC	Genetic algorithm based, flexible ligand, partial flexibility for protein	No	Commercial
GPCRautomodel	2012	INRA	Automates the homology modeling of mammalian olfactory receptors (ORs) based on the six three-dimensional (3D) structures of G protein-coupled receptors (GPCRs) available so far and performs the docking of odorants on these models	Available →	Free for academic use
HADDOCK	2003	Centre Bijvoet Center for Biomolecular Research	Makes use of biochemical and/or biophysical interaction data such as chemical shift perturbation data resulting from NMR titration experiments, mutagenesis data or bioinformatic predictions. Developed for protein-protein docking, but can also be applied to protein-ligand docking.	Available →	Freeware →
Hammerhead	1996	Arris Pharmaceutical Corporation	Fast, fully automated docking of flexible ligands to protein binding sites	No	Academic
ICM-Dock	1997	MolSoft	Docking program based on pseudo-Brownian sampling and local minimization	No	Commercial →
idTarget	2012	National Taiwan University	Predicts possible binding targets of a small chemical molecule via a divide-and-conquer docking approach	Available →	Freeware
iScreen	2011	China Medical University	Based on a cloud-computing system for TCM intelligent screening system	Available →	Freeware
Lead finder	2008	MolTech	Program for molecular docking, virtual screening and quantitative evaluation of ligand binding and biological activity	No	Commercial →
LigandFit	2003	BioVia	CHARMm based docking program	No	Commercial
LigDockCSA	2011	Seoul National University	Protein-ligand docking using conformational space annealing	No	Academic
LIGIN	1996	Weizmann Institute of Science	Molecular docking using surface complementarity	No	Commercial
LPCCSU	1999	Weizmann Institute of Science	Based on a detailed analysis of interatomic contacts and interface complementarity	Available →	Freeware
MCDOCK	1999	Georgetown University Medical Center	Based on a non-conventional Monte Carlo simulation technique	No	Academic
MEDock	2007	SIGMBI	Maximum-Entropy based Docking web server is aimed at providing an efficient utility for prediction of ligand binding site	Available →	Freeware
MolDock	2006	Molegro ApS	Based on a new heuristic search algorithm that combines differential evolution with a cavity prediction algorithm	No	Academic
MS-DOCK	2008	INSERM	Multi-stage docking/scoring protocol	No	Academic
ParDOCK	2007	Indian Institute of Technology	All-atom energy based Monte Carlo, rigid protein ligand docking	Available →	Freeware
PatchDock	2002	Tel Aviv University	The algorithm carries out rigid docking, with surface variability/flexibility implicitly addressed through liberal intermolecular penetration	Available →	Freeware
PLANTS	2006	University of Konstanz	Based on a class of stochastic optimization algorithms (ant colony optimization)	No	Free for academic use
PLATINUM	2008	Moscow Institute of Physics and Technology (State University)	Analysis and visualization of hydrophobic/hydrophilic properties of biomolecules supplied as 3D-structures	Available →	Freeware
PRODOCK	1999	Cornell University	Based on Monte Carlo method plus energy minimization	No	Academic
PSI-DOCK	2006	Peking University	Pose-Sensitive Inclined (PSI)-DOCK	No	Academic
PSO@AUTODOCK	2007	University of Leipzig	Particle Swarm Optimization (PSO) algorithms varCPSO and varCPSO-ls are suited for rapid docking of highly flexible ligands	No	Academic
PythDock	2011	Hanyang University	Heuristic docking program that uses Python programming language with a simple scoring function and a population based search engine	Available	Academic
Q-Dock	2008	Georgia Institute of Technology	Low-resolution flexible ligand docking with pocket-specific threading restraints	No	Freeware
QXP	1997	Novartis Pharmaceuticals Corporation	Monte Carlo perturbation with energy minimization in Cartesian space	No	Academic
rDock	2013	University of York/ Open source project	HTVS of small molecules against proteins and nucleic acids	No	Open source →
SANDOCK	1998	University of Edinburgh	Guided matching algorithm	No	Academic
Score	2004	Alessandro Pedretti & Giulio Vistoli	The Score service allows to calculate some different docking scores of ligand-receptor complex	Available →	Freeware
SODOCK	2007	Feng Chia University (Taiwan)	Swarm optimization for highly flexible protein-ligand docking	No	Academic
SOFTDocking	1991	University of California, Berkeley	Matching of molecular surface cubes	No	Academic
Surflex-Dock	2003	Tripos	Based on an idealized active site ligand (a protomol)	No	Commercial →
SwissDock	2011	Swiss Institute of Bioinformatics	Webservice to predict interaction between a protein and a small molecule ligand	Available →	Free webservice for academic use
VoteDock	2011	University of Warsaw	Consensus docking method for prediction of protein-ligand interactions	No	Academic
YUCCA	2005	Virginia Tech	Rigid protein-small-molecule docking	No	Academic

See also

• Drug design
• Katchalski-Katzir algorithm
• List of molecular graphics systems
• Macromolecular docking
• Molecular mechanics
• Protein structure
• Protein design
• Software for molecular mechanics modeling
• Molecular design software
• Docking@Home
• Ibercivis
• ZINC database
• Lead Finder
• Virtual screening
• Scoring functions for docking

External links

• Docking@GRID Project of Conformational Sampling and Docking on Grids : one aim is to deploy some intrinsic distributed docking algorithms on computational Grids, download Docking@GRID open-source Linux version
• Click2Drug.org - Directory of computational drug design tools.