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.[1] 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.

Schematic illustration of docking a small molecule ligand (green) to a protein target (black) producing a stable complex.
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.[2]

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”.[3] 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".[4]

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.[5][6][7] The second approach simulates the actual docking process in which the ligand-protein pairwise interaction energies are calculated.[8] 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.[9] 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.[10][11][12] 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

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

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:

Ligand flexibility

Conformations of the ligand may be generated in the absence of the receptor and subsequently docked[13] or conformations may be generated on-the-fly in the presence of the receptor binding cavity,[14] or with full rotational flexibility of every dihedral angle using fragment based docking.[15] Force field energy evaluation are most often used to select energetically reasonable conformations,[16] but knowledge-based methods have also been used.[17]

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.[18]

Multiple static structures experimentally determined for the same protein in different conformations are often used to emulate receptor flexibility.[19] Alternatively rotamer libraries of amino acid side chains that surround the binding cavity may be searched to generate alternate but energetically reasonable protein conformations.[20][21]

Scoring function

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:

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.[22] 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.[8]

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

Docking accuracy[24][25] 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.[23] 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. IC50, affinity or potency measurements). Only prospective studies constitute conclusive proof of the suitability of a technique for a particular target.[26]

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[27] or the Directory of Useful Decoys (DUD) for evaluation of virtual screening performance.[23]

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).[28]

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:

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
MOE 2005 Chemical Computing Group Supply a database of conformations or generate conformations on the fly. Choose between various scoring functions[30] and optionally constrain the generated poses to satisfy a pharmacophore query to bias the search towards known important interactions. Refine the poses using a forcefield based method with MM/GBVI[31] scoring or a fast grid based method. No Commercial
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; source codes available (Jaeyoon Chung; jychung@bu.edu) 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
MOLS 2.0 2016 University of Madras Software package for peptide modeling and protein-ligand docking No Open Source

See also

References

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