GShell Pack Xp Vista 1. WirelessMon 3. Skype 3. Wondershare Free YouTube Downloader 1. Auslogics Registry Defrag 4. NET Framework 3. Audio Converter 5. Spider Player Basic 2. Free FLV Converter 4. CDBurnerXP 4. ImgBurn 2. Spyware Doctor VSO Image Resizer 2. KeyboardLink 1. Any Video Converter 2. Dragon URL Sender Stardock IconPackager 4.
EarthDesk 4. BurnAware Free Edition 1. VMware Fusion 1. Bricopack Vista Inspirat Ultimate 2 StarBurn Blaze MediaConvert MySQL 5. Ubuntu 8. MathPro full version IrfanView 4. Vista skin pack 3. YoutubePick 1. FormatFactory 1.
Vsp 4. Vista Skin Pack 5. Adobe Lightroom Beta 3 For Windows 2. WinAmp 5. NOD32 3. ZoneAlarm Security Suite v7. Yahoo Messenger V9. Trillian Pro 3. Kaspersky Internet Security 8.
FlashGet v2. Safari 3. Windows Media Player 12 Beta Photoshop CS4 XnView 1. New--Internet Explorer7 pro2. LimeWire Pro 4. Download Accelerator Adobe Dreamweaver CS4 Beta Web Page Maker v3. Smart Defrag CloneDVD 2. IObit SmartDefrag 5. NET 3. DVDFab 5. BitDefender Total Security Beta 3 Norton Internet Security Adobe Acrobat Pro Extended 9. Gshell Pack Media Center Pack windows media center ported to xp MPlayer Full Package Caricature Photo To Cartoon Better File Rename 5.
LingvoSoft FlashCards 1. CoffeeCup Flash Firestarter 7. Window Washer 6. McAfee VirusScan Enterprise v8. Lock Folder XP v3. Youtube Download v3. Narcis Dictionary 5 Windows Doctor Pro Edition v1.
Blaze Media Pro 7. Autodesk Mental Ray Standalone v3. SmartSync Pro v2. River Media Center v Acronis True Image 11 Build Home Recover My Files 3. Encyclopaedia Britannica Ultimate Process Master 1. Download Managers AiO Acronis Disk Director Suite v Norton PartitionMagic 8. IsoBuster 2. System Mechanic 7. Multimedia Builder 4. King of software 3 DVDs A. O Agnitum Outpost Firewall Pro SQL Server Enterprise RAR Password Cracker 4.
Symantec Endpoint Protection v Dsl Speed 4. F-Secure Internet Security 8. Ashampoo Office 3. Site Studio 6. Invisible IP Map v2. Classic Menu for Office v3. VSO Image Resizer v1. Zoom Player 5. Nufsoft Nature Illusion Studio 2. Microsoft Connected services Framew0ork 3. Abacom sPlan 6. Error Repair Professional v3. English To Persian Talking Dictionary 1. Khazande3 YahooElite RegVac Registry Cleaner v5. PhoneBook Big-Killer-V60 Folder Crypt 2. Engineering Power Tools v2.
Desktop Magnifier for Windows v1. Zonealarm Pro 7. Sony Sound Forge v9. Online TV Player 4. FloorPlan 3D Design Suite 11 DeskCalc Business Pro 4. Cryptic Disk v2. New Folder Virus Remover Business Card Workshop Pro 3. PassMark WirelessMon v2. Remote Administrator Radmin v3. USB Over Network 2.
Norton Ghost The Bat! Internet Lock v5. AnyZip 1. Kaspersky Emergency CD Setup Factory v6. Remote Desktop Web Connection Autodesk MudBox 1. K-Lite Mega Codec Pack 4. QuickTime 7.
PDF to Word 1. Ashampoo WinOptimizer VirtualDrive ACD See CoffeeCup Flash Menu Builder 3. WinUtilities 6. Autodesk 3D Studio Max v Magix Music Maker Silver Full Ashampoo Photo Commander 6. PDF Password Remover v3. XP Tools 8. Macrovision InstallShield 12 Premier Edition Download Accelerator Premium v8.
Avira Premium Security Suite 7. Extra Video Converter 1. Karaoke Builder Studio 3. Saint Paint Studio 15 IDM UltraEdit v Color7 Video Convert Premier v8. Cyberlink PowerDirector 6. Real Player v. Flash Website Design Pro v1. Super Utilities Pro Magic Swf2Avi build 5. Internet Explorer 8 Trend Micro Internet Security Pro v16 Norton AntiBot v1. Windows worms doors cleaner v1. Pass2Go powered by RoboForm 4. U3 Oddcast Welcome 8. MedicAlert E-Record 9. EditPad Lite PuTTY for U3 IrfanView All Plugins Preclick PhotoBackPack IrfanView FxFoto Portable Pictures Shutterfly Studio Beta FotoAlbum Pro Portable Mozilla Thunderbird TotalNotes Protector Mobility Suite PocoMail PE Migo Personal Edition for U3 smart drives WinRAR for U3 Portable Party Poker Xfire TypingMaster Pro SignupShield Passwords Maxthon Browser WeatherBug For U3 FileZilla Pamela for Skype Basic Edition Skype Trillian Desktop Assistant MusicIP Anonymizer for U3 Pamela for Skpe Pro Edition Pamela for Skype Standard Edition FreedomBox Antivirus U3 Edition Challenger DmailerSync Plus U3 edition LapBack CryptoLock FILExtinguisher Safend Auditor CryptoMnemo Remora Guard Pro for U3 PowerBackup OLicense-Server Subsembly Wallet Desktop Remora Backup Pro for U3 Wallpaper Swapper Gaviri PocketSearch On2Share for U3 Package Backup DWG SmartLite WordLogic Predictive Keyboard Basic K-mac V1.
ProcX V1. PDF Viewers Keepass Password Mozilla Sunbird Quick Mailer Omziff Audacity Vlc GreatNews XNView Sage TrayURL Nvu WhoisThisDomain StartupList Country Codes Cpu-z WinAudit Convert Siw SyncPAppX PStart Registry Tweaker Restoration YamiPod Messenger v8. Portable Internet Download Manager 5. Portable WinXP Portable QuickTime Pro 7. PHP Designer v6. Portable MSN 8.
Portable Hard Disk Sentinel Professional v2. Portable Ashampoo Movie Shrink and Burn 2. Portable CyberLink Power Cinema 5. Portable Auslogics Disk Defrag 1. Portable FastStone Capture v5. Portable MS 0ff! Portable Netscape Navigator V.
Portable ICQ 6. Portable Yahoo Messenger V. Portable 0ff! Portable Adobe Audition 3. Portable Audio Recorder Pro v3. Portable RealPlayer v Portable Photodex ProShow Gold 3.
Portable FastStone Image Viewer 3. Portable JetAudio v7. Portable M! Portable Babylon Pro 7. Portable Foxit Reader V. Portable mIRC V. Portable DVD-Cloner 5. Portable CCleaner V. Portable Adobe PhotoShop Lightroom 1. Portable Your Uninstaller! Lang Portable 7-Zip 4. HyperSnap-DX 6. Portable Google Hacks v1. Portable FastStone Screen Capture 5.
Portable Google Talk v1. TuneUp Utilities Portable Edition Portable Microsoft Office OneNote Portable Kaspersky Internet Security 7. Complex Evolution v4. Portable Babylon Pro v7. Portable Power Archiver v Portal Internet Download Manager 5.
Microsoft Portable Word Winrar 3. Portable Active Password Changer v. Portable Microsoft Virtual PC BadCopy Pro 4. Portable Ashampoo Office v3. Portable Google Earth 4. Portable Recover Lost Data v3. Portable MigoSoft Registry Repair v4. Portable Nexus Radio 2. Visual Basic 6 Portable Portable 3D Studio Max WinRAR Unplugged v3.
Portable Windows Vista Portable WinZip Professional v11 Portable Windows Media Player 11 Portable ACDSee 8 Flash 8 Portable Portable Norton Systems Works Portable Adobe Fireworks CS3 Portable Orbit Downloader 2. IP Net Info v 1. Portable Adobe Illustrator CS3 Portable Everest Ultimate 4. Portable Yahoo Messenger v9. Portable iTunes 7. Portable TextAloud v2. Portable PowerISO v4. SuperAntiSpyware Pro 3.
Portable Dreamweaver 8. Portable Google Earth v4. Portable Winamp 5. ZoomIt 2. Finnix AliXe 0. EnGarde Secure Linux 3. Fedora Core 6 Test 2 6. QiLinux 2. PCLinuxOS 0. Hiweed Desktop 1. Tilix Linux 2. Freespire 1. OpenOffice Mandriva Linux Beta 2 SabayonLinux 3. Piebox Enterprise Linux 4 Update 4 Knoppix 4.
LinuxRAR 3. Firefox 1. Xine KPlayer Totem The base fragment is first docked into the active site by matching hydrogen bond pairs and metal and aromatic ring interactions between the ligand and protein. Then the remaining components are incrementally built-up in accordance with a set of predefined rotatable torsion angles to account for ligand flexibility. Its current version includes terms of electrostatic interactions, directional hydrogen bonds, rotational entropy, and aromatic and lipophilic interactions.
The interactions between functional groups are also taken into account through assigning the type and geometry for groups. The intrinsic mobility of proteins has been proved to be closely related to ligand binding behavior and it has been reviewed by Teague [ ].
Incorporating the receptor flexibility is significant challenge in the field of docking. Ideally, using MD simulations could model all the degrees of freedom in the ligand-receptor complex. But MD has the problem of inadequate sampling that we mentioned earlier. Another hurdle is its high computational expense, which prevents this method from being used in the screening of large chemical database.
In addition to the historic induced fit several theoretical models, conformer selection and conformational induction, have been proposed to illustrate the flexible ligand-protein binding process.
According to the definition given by Teague [ ], conformer selection refers to a process when a ligand selectively binds to a favorable conformation from a number of protein conformations; conformational induction describes a process in which the ligand converts the protein into a conformation that it would not spontaneously adopt in its unbound state.
In some cases, this conformational conversion can be likened to a partial refolding of the protein. Various methods are currently available to implement the receptor flexibility Table 3. This method may not include adequate flexibility.
Nevertheless, it has the advantage of computational efficiency as the receptor coordinates are fixed, simply by adjusting van der Waals parameters. Utilizing rotamer libraries [ , ] is another approach to modeling receptor flexibility. Rotamer libraries include a set of side-chain conformations which are usually determined from statistical analysis of structural experimental data.
The advantage of using rotamers is the relative speed in sampling, and the avoiding of minimization barriers. ICM Internal Coordinates Mechanics [ 61 ] is a program using rotamer libraries with the biased probability methodology [ ], coupled with Monte Carlo search of the ligand conformation. AutoDock 4 [ ] adopts a simultaneous sample method to deal with side chain flexibility. Several side chains of the receptor can be selected by users and simultaneously sampled with a ligand using the same methods.
Other portions of the receptor are treated rigidly with a grid energy map during sampling. Grid energy map introduced by Goodford [ 20 ] is used to store energy information of the receptor and simplify interaction energy calculation between ligand and receptor.
Still another way to deal with the protein flexibility is to use an ensemble of protein conformations, which corresponds to the theory of conformer selection [ , ]. A ligand is separately docked into a set of rigid protein conformations rather than a single one, and the results are merged depending on the method of choice [ ]. This method was originally implemented in DOCK, which generates an average potential energy grid of the ensemble [ ] and is extended in many programs in different ways.
For example, FlexE [ 38 ] collects multiple crystal structures of a certain protein, merging the similar parts while marking the dissimilar areas as different alternatives. During the incremental construction of a ligand discrete protein conformations are sampled in a combinatorial fashion. The highest scoring protein structure is selected based on a comparison between the ligand and each alternative.
Hybrid method is another practical strategy to model receptor flexibility. One example is Glide [ 33 ], a very popular program in the field of docking. Glide designs a series of hierarchical filters to search the possible poses and orientations of the ligand within the binding site of the receptor.
Ligand flexibility is handled by an exhaustive search of the ligand torsion angle space. Initial ligand conformations are selected based on torsion energies and docked into receptor binding sites with soft potentials.
Then a rotamer exploration is used to further model receptor flexibility [ 36 ]. IFREDA [ ] utilizes a hybrid method that combines soft potential and multiple receptor conformations, accounting for receptor flexibility. Other programs, like QXP [ 62 ] and Affinity [ 63 ], perform a Monte Carlo search of ligand conformations followed by a minimization step.
During minimization, the user-defined parts of the protein are allowed to move in order to avoid atom clashes between the ligand and receptor. SLIDE [ 53 ] is designed to incorporate flexibility with the ability to remove clashes by directed, single bond rotation of either the ligand or the side chains of the protein. An optimization approach based on the mean-field theory is applied to model induced-fit complementarities between the ligand and protein. Methods mentioned above either include only side chain flexibility or full flexibility of the receptor.
We have known that loops forming active sites play an important role in ligand binding. In some cases the loop may undergo dramatic conformational change whereas in other portions of the receptor there is little change upon ligand binding.
For this situation, side chain flexibility methods fail to sample the correct protein conformation and full flexibility seems to be a computational waste. Figure 1 shows superimposed crystal structures of triosephosphate isomerase as an example. However, the rest of the enzyme has no movement in comparison to their apo and holo structures. Several enzyme families also involve loop rearrangement within the active site responsible for ligand binding, such as Bromodomain, an extensive family related to acetyl-lysine binding, or Dihydrofolate reductase, responsible for the maintenance of the cellular pools of tetrahydrofolate, as well as other kinds of kinases [ , ].
In the next section, we present the Local Move Monte Carlo LMMC loop sampling method, a new approach which focuses on sampling ligand conformation within loop-containing active sites. Superimposed apo- in yellow and holo- in blue crystal structures of triosephosphate isomerase.
The 11 residue-loop composed of binding site is the only region that has large motion upon ligand binding in circle. The pioneering work on local move was done by Go and Scheraga [ ], who developed a solution for the system of equations defining the values of the six torsion angles that preserve the backbone bond lengths and angles. Hoffmann and Knapp first applied the local move method in a MC simulation of polyalanine folding that included a suitable Jacobian [ ], required for maintaining detailed balance.
They demonstrated that this method samples the conformational space more efficiently than single move [ ]. The method has been further tested on proline-containing peptides [ ], proteins and nucleic acids [ ]. Local move of a lipid tail. Six subsequent torsions change while keeping the rest of the chain to remain in its original position. The method generates loop conformations based on simple moves of the torsion angles of side chains and local moves of the backbones of loops.
To reduce the computational costs for energy evaluations, we developed a grid-based force field to represent the protein environment and solvation effect. Simulated annealing has been used to enhance the efficiency of the LMMC loop sampling and identify low-energy loop conformations. The prediction quality was evaluated on a set of protein loops with a known crystal structure that has been previously used by others to test different loop prediction methods.
The results show that this approach can reproduce the experimental results with root mean square deviation RMSD within 1. Figure 3 shows the loop structures of 2act sampled by the LMMC method. This LMMC loop prediction approach could be useful for flexible receptor docking.
In our future studies, we will develop our LMMC based molecular docking approach, which samples not only the side chains but also the backbone loops in the binding site of proteins and flexible ligands as well. Loop Structure of 2act produced by the local move MC method at K and followed by clustering to generate representative conformations.
Black stick represents the crystal loop structure, and gray wires represent the representative loop conformations. Abbreviate: MC, Monte Carlo. Molecular docking has been the most widely employed technique. Though the main application lies in structure-based virtual screening for identification of new active compounds towards a particular target protein, in which it has produced a number of success stories [ ], it is actually not a stand-alone technique but is normally embedded in a workflow of different in silico as well as experimental techniques [ ].
Several research groups focus on evaluating of the performance of various docking programs or on making improvements to the scoring functions when experimental testing has already been done. Such efforts could give meaningful guidance to choose the methodology for a particular target system.
Docking, combined with other computational techniques and experimental data, also could be involved in analyzing drug metabolism to obtain some useful information from the cytochrome P system [ - ], for example. In the following, three examples of successful applications of docking are presented.
DNA gyrase is a bacterial enzyme that introduces negative supercoils into bacterial DNA and unwinds of DNA, thus being studied as antibacterial target. Boehm et. Firstly, 3D complex structures of DNA gyrase with known inhibitors, ciprofloxacin and novobiocin, were carefully analyzed to get a common binding pattern, in which both inhibitors donate one hydrogen bond to Asp73 and accept one hydrogen bond from a conserved water molecule.
In addition, some lipophilic fragments should be included in the molecule to have lipophilic interaction with the receptor. Close analogs of these compounds were also considered, thus in total compounds were further tested using biased screening.
Consequently hits were selected and clustered into 14 classes of which 7 classes were proven to be the true and novel inhibitors. Subsequent hit optimization relied strongly on the knowledge of 3D structures of the binding site and eventually generated a series of highly potent DNA gyrase inhibitors.
Another example is focused on the validation of docking and scoring applied in cytochromes P and other heme-containing proteins [ ]. Docking against heme-containing complexes appears to be difficult because certain ligands coordinate directly to the heme iron atom and the precise energetics of this contact for different chelating groups needs to be properly balanced with other energetic terms, and in the case of the Ps, the environment above the heme group is very hydrophobic compared to other enzymes and some scoring functions and docking methods perform poorly on interactions driven entirely by lipophilic contacts.
In this study, 45 complexes from the PDB database comprising heme-containing proteins and ligands were selected. The native ligands were removed and then docked into the defined active cavities using the GOLD [ 65 ] software which employs genetic algorithms to generate ligand conformations.
The scoring functions used to rank the docking poses were Goldscore [ 32 ] and Chemscore [ 65 ]. Additionally, it is apparent from the data that the search algorithm was very unlikely to be responsible for the failure in docking. For the HTS a library of approximately , compounds from a corporate collection were screened. And the most active had an IC 50 value of 4.
After docking, the top-scoring molecules for the ACD and for the combined BioSpecs and Maybridge databases were considered for further evaluation.
A total of molecules were actually available, and after visual inspection compounds were chosen for testing. Structure-based docking therefore enriched the hit rate by fold over random screening. Receptor flexibility, especially backbone flexibility and movement of several key secondary elements of the receptor involving ligand binding and the catalyst, is still a major hurdle in docking studies.
Some methods to deal with side chain flexibility have been proven effective and adequate in certain cases. With respect to global flexibility, an ensemble of proteins is a popular solution which accords with the viewpoint of conformer selection. It requires an efficient way to obtain and select reliable protein structures used for docking, which means structures that the ligand can fit in should be included in the ensembles.
Besides, computational cost is another limitation for this method. LMMC could be an appropriate method for sampling a ligand within loop-containing active sites since loop tends to be more flexible and hard to model using existing approaches especially due to their possibly dramatic movements. Another advantage is the adjustment of the extent of flexibility. Either the side chain or full movement of the loop can be directly controlled by users. Scoring function is a fundamental component worth being further improved upon in docking.
Successful application examples show that computational approaches have the power to screen hits from a huge database and design novel small molecules. However, the realistic interactions between small molecules and receptors are still relied on experimental technology. Accurate as well as low computational cost scoring functions may bring docking application to a new stage. National Center for Biotechnology Information , U. Curr Comput Aided Drug Des. Author manuscript; available in PMC Jun 1.
Author information Copyright and License information Disclaimer. Copyright notice. See other articles in PMC that cite the published article. Abstract Molecular docking has become an increasingly important tool for drug discovery.
Introduction The completion of the human genome project has resulted in an increasing number of new therapeutic targets for drug discovery. Theory of docking Essentially, the aim of molecular docking is to give a prediction of the ligand-receptor complex structure using computation methods. Sampling algorithms With six degrees of translational and rotational freedom as well as the conformational degrees of freedom of both the ligand and protein, there are a huge number of possible binding modes between two molecules.
Table 1 Some sampling algorithms discussed in this paper. Algorithms Characteristic Reference Matching algorithms Geometry-based, suitable to VS and database enrichment for its high speed [ 43 - 45 ] Incremental construction Fragment-based and docking incrementally [ 30 , 49 , 50 ] MCSS fragment-based methods for the de novo design [ 55 , 56 ] LUDI fragment-based methods for the de novo design [ 57 ] Monte Carlo Stochastic search [ 58 , 59 ] Genetic algorithms Stochastic search [ 31 , 32 , 64 ] Molecular dynamics For further refinement after docking [ 68 - 70 ].
Open in a separate window. Scoring functions The purpose of the scoring function is to delineate the correct poses from incorrect poses, or binders from inactive compounds in a reasonable computation time. Table 2 Examples of scoring function formulae. Scoring function formulae Ref. For two atoms i, j, the pair-wise atomic energy is evaluated by the sum of van der Waals, hydrogen bond, coulomb energy and desolvation.
W are weighted factors for calibrate the empirical free energy. Docking methodologies Rigid ligand and rigid receptor docking When the ligand and receptor are both treated as rigid bodies, the search space is very limited, considering only three translational and three rotational degrees of freedom. Flexible ligand and rigid receptor docking For systems whose behavior follows the induced fit paradigm [ 28 , 29 ], it is of vital importance to consider the flexibilities of both the ligand and receptor since in that case both the ligand and receptor change their conformations to form a minimum energy perfect-fit complex.
Flexible ligand and flexible receptor docking The intrinsic mobility of proteins has been proved to be closely related to ligand binding behavior and it has been reviewed by Teague [ ]. Table 3 Some basic methods for including receptor flexibility. Method Description Advantage Disadvantage Program Soft potential Change vdW to allow for overlap between receptor and ligand atoms Computational efficiency. Easy to implement and use combined with other methods.
Inadequate flexibility. Describe flexibility in an implicit, rude and non- quantitative way. Avoid minimization barriers. Strong dependence on the database used. No backbone flexibility. ICM [ 61 ] Receptor side chain flexibility Sample both side chain and ligand conformations simultaneously using GA Relative computational efficiency. Model the effect that ligand make on binding site residues. Only selected side chains are involved.
AutoDock 4 [ ] Ensemble of protein conformations Docking ligand to a series of receptor structures which represent different conformational states. Include full and explicit flexibility. Expensive computational cost. Limited by protein conformations used in sampling. Figure 1. Figure 2. Figure 3. Figure 4. Application examples of molecular docking for drug discovery Molecular docking has been the most widely employed technique.
Concluding Remarks Receptor flexibility, especially backbone flexibility and movement of several key secondary elements of the receptor involving ligand binding and the catalyst, is still a major hurdle in docking studies. References [1] Jorgensen WL. The many roles of computation in drug discovery. AVG Internet Security 8. Caller ID Events 1. SPSS v6. ID ID-Pack Plus v7. Caller ID Events v1. ACDCSee v2. Instant ID v2. Simply ID v4. Character Studio r1. Mac Caller ID v1. Instant ID 2. Caller-ID Pro v1.
Airport ID v3. Caller ID 1 Talking Caller ID v6. Airport ID 3. ID Environment v3. Simply ID 2. Audio Caller ID v1. Splash ID v1. Audio Caller ID v2. Id photo pro Talking Caller ID v4. Id Imager 2. Agent 99 ID Webhacker v1. ID manager
0コメント