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Last Modified 7 Sep 2007 |
Molecular Modeling and Structure-based Drug Design Systems
The True Flexible Docking Simulation Program Package Docking Study with HyperChem Revision B1 - Carrying The Ultimate Technology In The Drug Discovery - From the Revision A3, some versions with a multiple-compound screening function are added to a product family. Compatible to the Protein Data Bank format versions 3.0 and 3.1.
The protein- and ligand-flexible docking program, Docking Study with HyperChem, is now available. This program is based on the excellent computational chemistry environment of HyperChem. The Revision A3 which is further sophisticated by the practical drug design in the medicinal chemistry is now available (A customer can always use the corresponding latest version of this package during a license period.). Moreover, Docking Study with HyperChem carries all functions for screening a drug candidate from a maximum 10,000 compound database.
Docking Study with HyperChem can predict the best docking mode of a complex between protein and compound, and can suggest the directionality of molecular design in the structure-based manner. Therefore, this program can support the high-level drug design such as the lead optimizations as well as can predict the lead compounds. The program can carry out the fully-automatic, comprehensive docking calculations under contributions of a protein flexibility (main chain and side chain flexibilities), as well as under contributions of a compound flexibility using full conformation search. Thus, the program can obviously deal with the induced fit effect of the protein system. This program supports the full graphical user interface basis (It is not necessary to edit and prepare a parameter file.). The program carries on the PIEFII (limited; simultaneous predictable maximum atoms: 500 atoms, ca. 40 residues) technology in the next-generation drug discovery. The package contains a specialized multifunctional browser, Dock Viewer, for viewing the result of the docking simulations. An initial structure of a trial compound can be automatically prepared using Mol Dimension program. Mol Browser can be used for browsing a 3D structure of a trial compound. New The Docking Study module program can automatically assign information on a trial compound such as a torsion and ring system. The torsion editor interface is useful for preparing the individual rotation angles. The structure of the stable complex between the trial compound and the protein system is represented by the OpenGL function of HyperChem (version 7.5 or the later). The browsing of the stable complexes is carried out under the fully-automatic rendering function in the level of a demonstration or a figure of a literature. In addition, the program can display the molecular surface (van der Waals surface) at a certain region such as the ligand-binding site together with the hit compounds. The following figures show the mesh surface (left) and the dot surface with the corresponding atom color (right), respectively. Dock Viewer program can simultaneously represent any molecular properties, e.g., molecular orbitals, charge densities, and electrostatic potentials, of a hit compound, rendering in many style. For example, the following figures show a hit compound formed the most stable complex with a target protein. At left-hand side of the figures, the highest occupied molecular orbital (HOMO) of the hit compound is shown together with a native ligand (white tubes) and the molecular surface (black mesh). At right-hand side of the figures, the isosurface of the electrostatic potentials of the hit compound is shown. Additionally, ONIOM Interface for Receptor in the Homology Modeling Professional for HyperChem package can analyze interactions of the stable complex between a hit compound and a target protein molecule using the high level ab-initio quantum chemistry calculations.
Advanced Technology Since the energy calculations do not use the grid algorithm, the program does not underestimate a critical interaction energy arising from a potential energy that is sharply lowered, thus giving a highly-precise structure of a stable complex between the protein and the compound. There are no limitations to kinds of protein molecule system, since the program does not use a probe atom by which the ligand-binding site of the target protein is pre-treated in order to simplify energy calculations in the grid algorithm. See the preferences for Docking Study with HyperChem to the known docking program adopting the grid algorithm. The program supports many force field calculations, i.e., MM+, Ambers, Amber2, Amber3, Amber94, Amber96, Amber99, OPLS, BIO+83, BIO+85, CHARMM19, CHARMM22, and CHARMM27 under the United Atom and All Atom conditions. Both the United Atom and the All Atom conditions can be applied to the desired parts of the protein and compound structures individually and simultaneously. These force field calculations can carry out under many minimization algorithm (Steepest Descent, Flether-Reeves, Polak- Ribiere, Newton-Raphson) supported by HyperChem, as well. The program can assign the atomic charges of a trial compound at each conformation using the single-point calculations of a certain semi-empirical molecular orbital method. Thus, the program can perform the latest docking simulations using the atomic charges altered by the structural changes. When the program is combined to the Gaussian Interface and ONIOM Interface of Homology Modeling for HyperChem, the program can provide the latest technology such as the QM:MM like docking simulations and the precise analysis of the obtained complex using the high-level ab initio quantum chemistry calculations such as a bond generation, a transition state analysis, and an excited state analysis. The protein flexibility can apply to the desired parts such as some residues in the ligand-binding site, hydrogen atoms, and entire structure. In addition, the flexibility of the protein molecule system can apply to any molecules such as water molecules, small molecules, and other biological molecules. This flexibility setting is completed by selecting a part of structure using selection tool provided in the package just before simulating. The protein system can contain any type of molecules such as metal, metal complex, small molecule, nucleic acid, and other biological molecules. The program can simulate the docking of compound, even though the ligand-binding site lies on several protein molecules. The program can freely modify the interaction energy equation to reproduce the structure-activity relationship via the multiple linear regression analysis. The program supports the restart function which can restart or start the docking simulations from a desired conformation without loss of the calculation precisions. The batch calculation of the docking simulations is also available when this function is used. Thus, the function is useful for searching precisely the best docking mode of the very flexible compound that has ten or more torsional bonds. Although the program carries an algorithm optimized to the docking simulations, many high-speed techniques developed for the virtual screenings such as the loose conformation search and conformational stability test techniques are also available. In the latest version, Docking Study with HyperChem with the multiple-compound screening function carries all functions for screening a drug candidate from a maximum 10,000 compound database. Moreover, these advanced technologies are based on our PIEFII technology which can precisely predict the protein-ligand interaction site and the potential ligand pharmacophore and scaffold. The following figures show the results of the PIEFII program for the cytochrome C. The second figure from the left hand side shows the predicted interaction points. The third figure from the left hand side shows the superposition between the predicted interaction points and the complexed protoporphyrin IX. As a result, the PIEFII program excellently reproduced a scaffold and chemical property of the protoporphyrin IX as well as the porphyrin-binding site. Moreover, the predicted interaction points excellently reproduced the position and conformation of two carboxyl moieties of the protoporphyrin IX. Thus, information obtained from the PIEFII program will lead to predict the native co-enzyme, even if the native co-enzyme is not known experimentally.
See the structure-based drug design using this program.
The following movie shows the result of the protein- and ligand-flexible docking simulations for a native ligand. In this study, the full conformation search for the ligand was performed under the flexible conditions of the side-chains of the protein system. In this movie, the original ligand complex to the receptor is shown in red (ball & stick) and the trial ligand obtained from the flexible docking simulations is shown in green (ball & stick). The structures of the flexible parts of the side chains are shown by tubes. In the present study, the simulations well reproduced an induced fit effect of the side chains of the receptor (In this movie, the individual receptor coordinates obtained from the docking simulations are superimposed on the original receptor coordinate).
The following figure shows the comparison between Docking Study with HyperChem (left) and a known docking program based on the grid algorithm (right). These results are obtained for the same docking data set under a default setting of these programs. The figure compares their interaction energies instead of the score values due to pure comparison of these programs. As shown in figure, Docking Study with HyperChem clearly dominates to all results such as the number of hit compounds, the ratio of precisions, and the structure-activity relationships (R). See more details.
Journal of Computer-Aided Molecular Design,14, 559-572, 2000.
Pamphlet (Japanese; 5 MB) SBDD Information (Japanese; 4 MB)
References An article entitled Development of the Structure-based Drug Design Systems, HMHC and DSHC has been published in the first issue of Molecular Science electronic journal. M Tsuji, Molecular Science, 1, NP004, 2007.
Sales Performance Domestic Medicinal Company
Module Programs Control Center PIEFII Limited (Simultaneous predictable maximum atoms: 500 atoms, ca. 40 residues) Docking Study Mol Browser New
* Simultaneous predictable maximum atoms: 500 atoms, ca. 40 residues. ** Although the program is non-limited version, the available number of compounds depends on the Docking Study and Mol Dimension module programs.
Recommended Minimum System Requirements Processor: Intel Pentium III, Pentium 4, Celeron, Core2Duo, or Xeon (2 GHz recommended; AMD processor is unidentified) Operating System: Microsoft Windows 98, NT4, 2000, XP, or Vista* (WindowsXP Professional or Vista recommended) Memory (RAM): 256 MB (512 MB recommended) Monitor: XGA (SXGA recommended) Video Card: OpenGL board Other: HD (30 MB for storage); CD-ROM drive; Mouse; Network Interface * There is a case wherein communication with HyperChem will be interrupted by operating an inactive window under the Windows Aero condition.
Software Requirements HyperChem*: 6.x/7.x/8.03 (Windows version; Student edition is unidentified). Due to absence of the force field parameters for a small molecule, the version 5.x of HyperChem is not recommended. TclPro1.2: TclPro1.2 (Windows version) is necessary to run Docking Study with HyperChem. TclPro1.2 is available on the Web free of charge. * In the case of Ambers, Amber2, Amber3, BIO+83, and BIO+85 force fields of the HyperChem version 6.x, there are cases wherein the parameters of compound are insufficient.
Description Docking Study with HyperChem is a package of Tcl/Tk programs. These programs are compiled by the TclPro1.2 compiler. Thus, in order to run the package, you must install TclPro1.2 in your Windows system, prior to the installation of the package. A substantial Online-Help (English) is available from individual programs in the package. The package includes one copy of user's manual (presently Japanese Language Only), Docking Study with HyperChem Manual. Important: When you installing the software, please make sure that HyperChem and TclPro1.2 have been installed in your system.
Evaluation A free package, Molecular Modeling Tools for HyperChem, is available. Please try it on evaluating our products.
* HyperChem is a registered trademark of Hypercube, Inc.
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