Computational molecular docking is a research technique for predicting whether one molecule will bind to another, usually a protein. Protein-protein, protein-DNA and protein-ligand docking predictions are all performed, though the techniques employed in each area are highly various. Protein-ligand docking is done by modelling the interaction between protein and ligand: if the geometry of the pair is complementary and involves favorable biochemical interactions, the ligand will potentially bind the protein in vitro or in vivo. It has been suggested that this article or section be merged with Protein-protein interactions. ... Protein-ligand docking is a molecular modelling technique. ... The backbone dihedral angles are included in the molecular model of a protein. ... This article or section is in need of attention from an expert on the subject. ... Wiktionary has a definition of: In vitro In vitro (Latin: within glass) means within a test tube, or, more generally, outside a living organism or cell. ... In vivo (Latin for (with)in the living). ...

Applications

A binding interaction may mean that the ligand inhibits the protein's function or acts as an agonist. Docking is most pertinent to the field of drug design—most drugs are small molecules, and using a computational approach allows researchers to quickly screen large databases of potential drugs (e.g., the ZINC database of compounds for virtual screening) against protein targets such as HIV reverse transcriptase. Traditional discovery of drug candidates occurs by chance or through painstaking work in the lab. For example, virtual screening and related combinatorial chemistry techniques are particularly important in searching for new antibiotics as strains of resistant bacteria increasingly appear due to overuse of antibiotics. HIV protease in a complex with the protease inhibitor ritonavir. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Agonists An agonist is a substance that binds to a receptor and triggers a response in the cell. ... Drug design is the approach of finding drugs by design, based on their biological targets. ... Species Human immunodeficiency virus 1 Human immunodeficiency virus 2 Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS, a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections). ... Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs act at different stages of the HIV life cycle. ... Combinatorial chemistry involves the rapid synthesis and/or the computer simulation of a large number of different but structurally related molecules. ...

The mechanics of docking

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 less often, NMR spectroscopy. 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. X-ray crystallography or single-crystal X-ray diffraction is an analytical technique which uses the diffraction pattern produced by bombarding a single crystal with X-rays to solve the crystal structure. ... Pacific Northwest National Laboratorys high magnetic field (800 MHz) NMR spectrometer being loaded with a sample. ... In computer science, a search algorithm, broadly speaking, is an algorithm that takes a problem as input and returns a solution to the problem, usually after evaluating a number of possible solutions. ... The term molecular mechanics refers to the use of Newtonian mechanics to model molecular systems. ...

The search algorithm

The search space consists of all possible orientations and conformations of the protein paired with the ligand. With present computing 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 a flexible ligand, and several are attempting to model a flexible protein receptor. Each "snapshot" of the pair is referred to as a pose. There are many strategies for sampling the search space. Here are some examples: In search algorithms, search space is the collection of possible solutions to a problem, and incorporates some notion of distance between candidate solutions; the correct solution will be near the optimal point in this hypothetical space, which may be envisioned as having a dimension for each variable. ... In chemistry, a chemical conformation is the spatial arrangement of atoms in a molecule. ... Flight dynamics is the study of orientation of air and space vehicles and how to control the critical flight parameters, typically named pitch, roll and yaw. ... Granularity is the extent to which a system contains discrete components of ever-smaller size. ...

• Use a coarse-grained molecular dynamics simulation to propose energetically reasonable poses
• Use a "linear combination" of multiple structures determined for the same protein to emulate receptor flexibility
• Use a genetic algorithm to "evolve" new poses that are successively more and more likely to represent favorable binding interactions. niranjan

Molecular dynamics (MD) is a form of computer simulation where atoms and molecules are allowed to interact for a period of time under known laws of physics. ... In mathematics, linear combinations are a concept central to linear algebra and related fields of mathematics. ... A genetic algorithm (GA) is an algorithm used to find approximate solutions to difficult-to-solve problems through application of the principles of evolutionary biology to computer science. ...

The scoring function

The scoring function takes a pose as input and returns a number indicating the likelihood that the pose represents a favorable binding interaction.

Most scoring functions are physics-based molecular mechanics force fields that estimate the energy of the pose; a low (negative) energy indicates a stable system and thus a likely binding interaction. An alternative approach is to derive a 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. The term molecular mechanics refers to the use of Newtonian mechanics to model molecular systems. ... A force field is used to minimize the bond stretching energy of this ethane molecule. ... The Protein Data Bank (PDB) is a repository for 3-D structural data of proteins and nucleic acids. ...

There are a lot of structures from X-ray diffraction for complexes between proteins and high affinity ligands, but very few for low affinity ligands as these do not stay bound for long enough to be seen. Scoring functions trained with this data can dock high affinity ligands correctly, but they will also give plausible docked conformations for ligands that really are inactive. 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. X-ray crystallography is a technique in crystallography in which the pattern produced by the diffraction of x-rays through the closely spaced lattice of atoms in a crystal is recorded and then analyzed to reveal the nature of that lattice. ... A false positive, also called false alarm, exists when a test reports, incorrectly, that it has found a signal where none exists in reality. ...

One way to reduce the number of false positives is to recalculate the energy of the top-hit poses using a higher resolution (and therefore slow) technique like Generalized Born or Poisson-Boltzmann methods^[1]. However, typically the researcher will screen a database of tens to hundreds of thousands of compounds and test the top 60 or so in vitro, and to identify any true binders is still considered a success.

See also

• Drug design
• Molecular mechanics
• Protein structure
• Rosetta@home
• Katchalski-Katzir algorithm

Drug design is the approach of finding drugs by design, based on their biological targets. ... The term molecular mechanics refers to the use of Newtonian mechanics to model molecular systems. ... Proteins are an important class of biological macromolecules present in all biological organisms, made up of such elements as carbon, hydrogen, nitrogen, oxygen and sulfur. ... Rosetta@home (website) is a distributed computing project, run by the Baker Laboratory at the University of Washington, aiming to solve the protein structure prediction problem. ... Katchalski-Katzir algorithm is a algorithm for molecular docking of rigid molecules, developed by Ephraim Katchalski-Katzir. ...

External links

• WISDOM stands for World-wide In Silico Docking on Malaria A large scale virtual screening effort on computational grid infrastructures aims at finding new drugs for malaria and other neglected diseases.
• CureCancer Screensaver Lifesaver A large-scale distributed docking effort by Oxford University, NFCR and UnitedDevices, applying the LigandFit software, aimed to finding drugs for pancreatic cancer and leukemia.
• Quantum Molecular Docking Software A docking program developed by Quantum Pharmaceuticals
• FIGHTAIDS@Home A project by The Scripps Institute, applying the AutoDock drug-docking software towards discovery of new HIV therapies
• Rosetta@Home A distributed computing project, aiming to improve the Rosetta software for protein prediction, design and docking
• ClusPro A docking program developed by the Camacho group at Boston University
• SmoothDock A docking prediction program and Online server by Carlos J. Camacho and P. Christoph Champ at University of Pittsburgh
• AutoDock A docking program developed by the Olson group at The Scripps Research Institute
• DOCK A docking program developed in the Kuntz and Shoichet groups at the University of California, San Francisco
• eHiTS A docking program developed by SimBioSys in Toronto, Canada
• FRED A docking program developed and commercialized by OpenEye Scientific Software in the US
• GOLD A docking program produced by the CCDC in Cambridge, UK
• Glide A docking program developed and commercialized by Schrödinger in the US
• FlexX A docking program developed by BioSolveIT in Germany
• Molegro Virtual Docker A docking program developed by Molegro in Denmark
• ICM A docking program developed by Prof. Ruben Abagyan and Dr. Maxim Totrov at Molsoft LLC
• FLexscreen A docking program, which accounts for flexibility and uses stochastic tunneling method, developed at the group of Wolfgang Wenzel at the Forschungszentrum in Karlsruhe, Germany FZK

For similarly-named academic institutions, see Boston (disambiguation). ... The University of Pittsburgh, commonly referred to as Pitt, is a state-related, doctoral/research university in Pittsburgh, Pennsylvania. ... TSRIs Beckman Center for Chemical Sciences The Scripps Research Institute (TSRI) is a medical research facility that focuses on research in the basic biomedical sciences. ... UCSF in 1908, with the streetcar that used to run on Parnassus Avenue The University of California, San Francisco (UCSF) is one of the worlds leading centers of health sciences research, patient care, and education. ... There are very few or no other articles that link to this one. ... United States may refer to: Places: United States of America SS United States, the fastest ocean liner ever built. ... Geography Status City (1951) Region East of England Admin. ... United States may refer to: Places: United States of America SS United States, the fastest ocean liner ever built. ...

References

1. ^  Feig, et al. (2004). Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures. J Comput Chem, 25(2):265-84.