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. Table 1 Molecular docking software Pedro H. Torres, et al. Various docking software is under developed that will increase the biological accuracy in modeling docking processes.
Predicting interactions between proteins and ligands using computer-aided methods or artificial intelligence AI models has attracted great interest in recent years. Deep learning paired with drug docking and molecular dynamics simulations identify small molecules to identify with precision the correct ligand conformation within the binding pocket of a given target molecule.
Figure 1 Overview of Molecular Docking. To perform a successful 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, NMR spectroscopy or cryo electron microscopy cryo-EM , but can also derive from homology modeling construction. The linked-fragment approach of Verlinde and coworkers are based on shape descriptors Verlinde et al.
Caflisch and coworkers used MCSS maximal common substructure search against HIV protease to map a binding site and constructed peptide inhibitors by building bonds to connect the various minima they found Caflisch et al. FlexX uses a tree-search technique for placing the ligand into the active site, incrementally starting with the base fragment Rarey et al.
Unlike other docking programs, Glide performs a complete systematic search of the conformational, orientational, and positional space of the docked ligand with the OPLS-AA force field Optimized Potentials for Liquid Simulations. The best possible conformation is further refined using Monte Carlo sampling Friesner et al. Further, a surface-based molecular similarity method was implemented in Surflex Jain to rapidly generate suitable putative poses for molecular fragments using the Hammerhead docking system Jain In addition, a multi-objective docking strategy, MoDock, has been proposed to further improve the pose prediction with the available scoring functions divided into the following three types: force field-based, empirical-based, and knowledge-based.
The results obtained indicate that the multi-objective strategy can enhance the pose prediction power of docking with the available scoring functions Gu et al. Surprisingly, both Dock as well as FlexX were not able to produce a reasonable solution for at least three TK ligands IdU 5-iododeoxyuridine , hmtt 6-[6-hydroxymethymethyl-2,4-dioxo-hexahydro-pyrimidinyl-methyl]methyl-1H-pyrimidin-2,4-dione , and mct North -methanocarba-thymidine for Dock; hmtt, ganciclovir, and penciclovir for FlexX.
On the other hand, DOCK failed completely to predict a reliable pose for raloxifene. However, no relationship was found between the docking accuracy and ranking score with these programs Bissantz et al.
In , five docking programs, DOCK 4. The results revealed that ICM provided the highest docking accuracy against these receptors, with a value of 0. All these docking programs performed well with small hydrophobic ligands, while the performance of GOLD and Surflex remained roughly unchanged. In the same year of , three highly regarded docking programs, namely, Glide, GOLD, and ICM, were evaluated on a vertex dataset of diverse protein—ligand complexes to predict their ability to reproduce crystallographic binding orientations.
In regards to ligand complexity, all these docking programs performed well, with the ligands having ten or fewer rotatable bonds. Evaluation of known crystal structures of 40 zinc-dependent metalloproteinase ligand complexes showed the lowest energy conformations by GOLD and DrugScore with a proper ZBG zinc binding group binding.
If the RMSD limit is increased to 2. At the RMSD cutoff of 2. Later, ten docking programs and 37 scoring functions were analyzed against seven protein types to predict the binding mode, lead identification using virtual screening, and lead optimization. Studies also showed that GOLD performed well with hydrophilic targets where there is some lipophilic character in the active site i. Furthermore, seven commonly used programs were evaluated on the PDBbind database with protein complexes Plewczynski et al.
The level of correlation for hydrophobic molecules is 0. In , four popular docking programs were evaluated, Glide version 4. Out of these four docking programs, GOLD and Surflex processed well with the dataset, while Glide and LigandFit failed to process 25 and 8 complexes, respectively. Recently, ten docking programs were evaluated.
On the basis of the results for the top scored poses, the performance of the academic programs conform to the following order: LeDock The averaged success rates of the commercial docking programs in predicting the top scored poses and best poses are This shows that all these docking algorithms were able to explore the conformational space to generate correctly docked poses in the binding pockets sufficiently well on a diverse set of protein—ligand complexes.
In general. Glide performs well with diversified binding sites and flexibility of the ligand, while ICM and GOLD perform significantly poorer when binding sites are mainly influenced by hydrophobic contacts. These results also show that the difference between the commercial and academic programs was not obvious, even though the capability of predicting the ligand binding poses by the commercial programs is slightly better than that of the academic programs from a global perspective.
Structure-based drug design is a powerful technique for the rapid identification of small molecules against the 3D structure of the macromolecular targets available by either X-ray, NMR, or homology models.
Because of abundant information regarding the sequences and structures of the proteins, the structural information of individual proteins and their interactions became very important for further drug therapy.
Although many docking programs exist for conformational searching and binding pose prediction, the scoring functions are not accurate and need to be improved further. Nevertheless, despite the drawbacks of each docking strategy, active research is taking place to address all the issues regarding scoring, explicit protein flexibility, explicit water, etc.
Even in the absence of knowledge regarding the binding site and limited backbone movements, a variety of search algorithms have been developed for protein—protein docking over the past two decades. As rigid body docking can systematically explore the shape complementarity between proteins, this may not work well for docking the proteins that are crystallized separately.
Thus, a high-resolution protocol is very much needed to understand the basic principles to detect the underlying mechanism of protein—protein interactions and actual binding with other proteins.
Rescoring using empirical potentials may not even eliminate all the false-positives. Even fine tuning of individual protein—protein interactions by redesigning the protein interface depends on the accurate structure of the protein complex generated by high-resolution docking protocols. Although, ZDOCK, rDOCK, and HEX provided the results with high docking accuracy, the provided complexes are not highly useful to design the inhibitors for the protein interfaces due to constraints in rigid body docking.
Due to this, flexible approaches were developed that generally examine very limited conformations compared to the rigid body methods. These docking methods predict binding poses most likely to occur on the broad surface regions and then define the sites into high-affinity complex structures. The best example is the HADDOCK software, which has been quite successful in resolving a large number of accurate models for protein—protein complexes.
One good example is the study of the complex formed between plectasin, a member of the innate immune system, and the bacterial wall precursor lipid II. The study has clearly identified the residues involved at the binding site between the two proteins, providing valuable information for the design of novel antibiotics.
However, the absolute energies associated with the intermolecular interaction are not estimated with satisfactory accuracy by the current algorithms. The major issues of solvent effects, entropic effects, and receptor flexibility still need to be handled with special attention. The realistic interactions between small molecules and receptors still rely on experimental technology. Moreover, using the current docking methods, although they discriminate between different ligands based on binding affinity with high accuracy, the mode of binding, solvent effects, entropic effects, and effects of protonation states of the charged residues in the active site are still major problems.
With the aid of community efforts such as CAPRI Critical Assessment of PRediction of Interactions , a large number of docking algorithms and their limitations were overcome with benchmark testing. But the problem of flexibility is still under investigation and with the accelerated pace of research in this area, it will be tackled soon in the near future. Nataraj S. Pagadala declares that he has no conflict of interest. Khajamohiddin Syed declares that he has no conflict of interest. Jack Tuszynski declares that he has no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors. National Center for Biotechnology Information , U.
Journal List Biophys Rev v. Biophys Rev. Published online Jan Pagadala , 1 Khajamohiddin Syed , 2 and Jack Tuszynski 3, 4. Author information Article notes Copyright and License information Disclaimer. Pagadala, Email: moc. Corresponding author. Received Nov 13; Accepted Dec This article has been cited by other articles in PMC. Abstract Molecular docking methodology explores the behavior of small molecules in the binding site of a target protein.
Keywords: Rigid body docking, Flexible docking, Docking accuracy. Introduction In modern drug discovery, protein—ligand or protein—protein docking plays an important role in predicting the orientation of the ligand when it is bound to a protein receptor or enzyme using shape and electrostatic interactions to quantify it.
Rigid body docking Rigid body docking produces a large number of docked conformations with favorable surface complementarity, followed by the reranking of the conformations using the free energy of approximation. Accuracy of rigid body docking Docking was considered successful if the binding of a ligand into its active site was closer than a given threshold from the X-ray solution. Flexible docking In standard virtual docking studies, ligands are freely docked into a rigid receptor.
Conclusions Structure-based drug design is a powerful technique for the rapid identification of small molecules against the 3D structure of the macromolecular targets available by either X-ray, NMR, or homology models. Compliance with ethical standards Conflict of interest Nataraj S. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
Structure-based design of a cyclophilin—calcineurin bridging ligand. DOCK 6: impact of new features and current docking performance. J Comput Chem. F2Dock: fast Fourier protein—protein docking. ParaDock: a flexible non-specific DNA—rigid protein docking algorithm. Nucleic Acids Res.
The protein data bank. ASuite is another free, portable application launcher for Windows similar to PStart. It displays your program shortcuts, files, folders, and web page links in a tree structure on the List tab.
ASuite uses relative paths, like PStart, so your programs, files, and folders can be opened on any Windows computer without issue. The program requires installation, but it can be installed to any drive, local or removable. Use SE-TrayMenu to gain quick access to most frequently used applications and system commands using a customizable popup menu from the Windows system tray. Quickly add programs, documents, folders, and internet links to the menu using drag-and-drop.
The menu is also completely customizable. See our article about SE-TrayMenu for more information. Portable Start Menu is a simple and free application launcher for Windows similar to the Start menu that can be installed on a USB flash drive or a local hard drive. Organize your programs in a simple menu system and launch them using a system tray icon. Portable Start Menu also allows you to automatically mount and dismount TrueCrypt containers.
The following programs are application launchers that either replace or enhance the Windows Start menu, Taskbar, or Desktop.
We also list a launcher that comes in the form of a Gadget for the Windows 7 desktop. Jumplist-Launcher is a free Windows program launcher that allows you to consolidate applications on the Taskbar, combining multiple applications into one jump list. You can add up to 60 programs in custom groups inside one jump list and drag and drop shortcuts, files, and folders onto the Jumplist-Launcher setup dialog. For more information, see our article about Jumplist-Launcher.
Once you install 7Stacks, an icon is added to the desktop that allows you to easily create new stacks as shortcuts on the desktop. You can then pin up to 10 different stacks to the Taskbar.
You can create stacks from special folders, such as My Documents, or from ordinary folders on your hard drive. See our article about 7Stacks for information. The launcher can be accessed through the system tray, using a hotkey, or by clicking the middle mouse button.
It is portable and can use relative paths, making it useful as an application launcher for portable programs on USB flash drives. The look of the launcher can be customized using skins and you can use custom picture files. ViPad is a free application launcher and desktop organization tool for Windows that allows you to gather your favorite program shortcuts, website links, system tools shortcuts, files, folders, etc. You can even categorize the items onto personalized tabs. Use drag-and-drop to put items on the launcher and to rearrange the items.
Windows 7 App Launcher Gadget provides a very small application launcher that displays on your desktop as a gadget. You can drag and drop program shortcuts, files, and folders directly onto the gadget. You can also add favorites from Firefox, Opera, and IE to the gadget so you can quickly access websites.
If you use Linux, check out the following useful application launchers that are only available for Linux. It can also be used to keep track of open windows. AWN is highly customizable and fits perfectly into your Ubuntu theme. Gnome-Do is a keyboard-oriented program for Linux that allows you to quickly search for many items in your GNOME desktop environment, such as applications, Firefox bookmarks, files, etc.
It is plugin-based, allowing you to easily extend it to handle new items and actions. Docky is a dock application for Linux that makes opening common applications and managing windows quicker and easier. Besides being an application launcher, Docky can also manage your running applications and host various docklets, including a CPU monitor, weather report, and clock. Applications can integrate with Docky to add extra items to their context menus or modify their icons to display more information.
The following application launchers are for those of you who prefer using the keyboard over the mouse. They make launching applications and opening files quick and easy.
Display the FARR window using a custom hotkey, and then just start typing the first letters of the application, file, or folder you want to find and the results display instantly.
You can also use FARR to run web searches, send email, manipulate files, and much more. Plugins, add-ons, and extensions are also available for FARR. Launchy is a free utility for Windows, Linux, and Mac designed to help you launch your documents, files, folders, and bookmarks with just a few keystrokes.
It also indexes the programs in your Start menu in Windows, providing quick access to your favorite programs. Launchy opens as a small window in which you type your search term. The results display below the window as you type. However, adding apps to this dock can be difficult.
You have to create a shortcut for an app and then drag it to the dock to add it. While this dock app comes with an auto-hide feature, you do have to be careful when choosing where to place this dock on your screen.
If your dock and Taskbar are both at the bottom of your screen, you can accidentally open apps from your Taskbar when you are trying to click on the dock. However, you can always move this dock up or hide your Taskbar. If you want to know how to hide your Taskbar and more, check out our guide on how to customize your Taskbar.
Unlike most dock apps, ObjectDock gives you access to a main dock, or what they call a Quicklaunch Dock, as well as a Tabbed Dock. The Quicklaunch Dock works just like the dock on your Mac, while the Tabbed Docks gives you another location to add shortcuts for your programs, documents, links, and other files and folders. You can set the Quicklaunch Dock to show all your open applications, all your running windows, minimized windows, and even show system tray icons.
You can also customize the position, size, style, color, and animation effects of the dock. For example, you can use a zoom effect like the Mac dock has, or you can make your icons glow when you hover your mouse over them.
Plus, when you hover over an app, you can see a preview of all the windows you have open for that app.
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