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Figure 2.34. Ligand, methotrexate bound to the protein dihydrofolate reductase visualized in MarvinSpace. Detailed view of the binding pocket. The surface is colored by residue type and it is transparent. Behind it the ball and stick representation of the protein is seen. Lengths of some hydrogen bonds are monitored. Two pharmacophore regions are also defined; an acceptor (red sphere) and a hydrophobic region (large yellow sphere), these are also semi-transparent. Image courtesy of ChemAxon

Figure 2.35. Web-based chemistry search tool that combines multiple search criteria to query compound structures and related data. Uses Marvin for structure input and viewing and JChem Base for structural search, designed by Zhenbin Li of Neurogen Corporation

2.8 Chemical Computing Group

I. Chemical Computing Group (

II. Product Summary: The Chemical Computing Group (CCG) offers its MOE (Molecular Operating Environment) computational software platform for life science applications such as Bioinformatics, Chemoinformatics, High-Throughput Discovery, Structure-Based Design, Protein Modeling, Molecular Modeling and Simulations, and Methodology Development and Deployment.

III. Key capabilities and offerings:

a. Bioinformatics: This set of tools allows the access to protein crystallography data for structure analysis, protein structure determinations from amino acid sequences, and protein structure predictions.

i. Protein Structure Database. This database is a curated version of the Protein Data Bank containing searchable fields such as Code, Header, Compound, Title, HET groups, resolution, etc.

ii. Structural Family Database. GCC has processed and clustered the proteins of the Protein Data Bank to provide a database of structural families.

iii. Fold Identification. A fold detection algorithm allows for the searching and identification of structurally similar proteins in the Structural Family Database.

iv. Multiple Alignment. The multiple protein alignment methodology implemented in MOE can correlate the sequence and structures of large collections of proteins.

v. Structural Family Analysis. Allows the study and correlation of conserved features and differences between related protein structures and homologous sequences.

b. Chemoinformatics: This suite allows the manipulation and analysis of large sets of chemical structures.

i. Molecular Databases. These spreadsheet-based databases can store and manipulate large number of compounds. The structures can be imported through several formats and structures can be automatically stripped from salts and solvents.

ii. Molecular Descriptors. This system can calculate 400 types of molecular descriptors (e.g., topological indices, structural keys, physical properties, topological polar surface area) and use custom-made descriptors using MOE's built-in Scientific Vector Language.

iii. QSAR/QSPR Predictive Modeling. This set of tools permits the construction of models to predict activity, cluster and filter collections of compounds, and carry out diversity and similarity assessments.

iv. Molecular Fingerprinting / Clustering / Similarity Searching. 2D and 3D molecular fingerprinting systems including MACCS, 3D shape, and pharmacophore fingerprints for similarity searching, clustering and diversity analysis.

v. High Throughput Conformational Search. Keeping a database of molecular fragments, the system is capable of executing fast conformational searches on large collection of compounds.

vi. 3D Pharmacophore Search. The system allows the construction of queries of pharmacophoric features working in sync with the conforma-tional database mentioned above.

vii. 3D Pharmacophore Elucidation. An application for automatically generating pharmacophore queries based on acitivity data.

viii. Suite of SDF file processing utilities for compound database management.

ix. 2D depiction tools for reports and presentations.

c. High-Throughput Discovery: MOE comes with an integrated set of tools for the handling and process of combinatorial compound libraries coming from combinatorial chemistry and high-throughput screening.

i. Molecular Descriptors. Same as described in CCG's Chemoinformatics section (b).

ii. HTS-QSAR. All molecular structures are processed and structure-property correlations are determined using linear or probabilistic methodologies.

iii. Combinatorial Library Enumeration. MOE comes with an integrated enumerating engine to construct combinatorial compound libraries with chirality awareness.

iv. Focused Combinatorial Library Design. Focused combinatorial libraries are designed by incorporating QSAR and ADME models to propose compounds with a higher probability of desired biological activity. The compounds are enumerated using a product-based approach.

v. Diverse Combinatorial Library Design. Large sets of diverse combinatorial libraries can be product-based enumerated using a Monte Carlo sampling technique to extract diverse compound subsets.

d. Structure-Based Design: Using crystallographic data of macromolecules

MOE can assist in the study, visualization and identification of active sites and receptor-ligand interactions to design and screen new ligand candidates.

i. Active Site Detection. Using a geometric algorithm, MOE can detect candidate protein-ligand and protein-protein binding sites.

ii. Probabilistic Contact Potentials. The system maps and identifies hydropho-bic and hydrophilic contact sites between target and ligand determining inter-atomic distances and angles.

iii. Multi-Fragment Search. The program populates a large number of chemical fragments in a predetermined active site where the fragments are minimized, clustered and scored for their analysis.

iv. Ligand-Receptor Docking. Module-based docking protocol for placing ligands in biding sites. Docking modules are extensible allowing for easy incorporation of different placement algorithms and scoring methods. Solvation effects can be included in the calculations.

v. 3D Pharmacophore Elucidation. An application for automatically generating pharmacophore queries based on activity data.

vi. 3D Pharmacophore Search. The system allows the construction of queries of pharmacophoric features working in sync with the embedded conformational database to identify most promising ligands.

e. Protein Modeling: MOE comes with an integrated protein tool set for protein structure prediction.

i. Homology Search. The system searches a database of structural families calculated by 3D clustering the Protein Data Bank for sequence-to-structure predictions.

ii. Multiple Alignment. The multiple protein alignment methodology implemented in MOE can correlate the sequence and structures of large collections of proteins.

iii. Structural Family Analysis. Allows the study and correlation of conserved features and differences between related protein structures and homologous sequences.

iv. Structure Prediction. The system can take an amino-acid sequence input, match the sequence against experimentally determined backbone structures, and refines the predicted structure using the AMBER '89/'94/'99, CHARMM22/27 or Engh-Huber forcefields. v. Structural Quality Assessment. To assess the reliability of predicted structures MOE uses statistical measures derived from X-ray crystallo-graphic data. Diagnostic measures include Ramachandran and Chi plots.

f. Molecular Modeling and Simulations: In order to construct, study and model chemical structures MOE has embedded molecular editors and validated forcefields.

i. Molecular Builders and Data Import/Export. MOE comes with integrated building interfaces to create or edit small molecules, proteins, carbohydrates, DNA and crystal structures. The system can also import and export structures in many standard file formats.

ii. Molecular Mechanics. MOE's engine integrates and uses different force-fields such as AMBER '89/'94/'99, CHARMM22/27, MMFF94, MMFF94s, OPLS-AA and Engh-Huber.

iii. Implicit Solvent Electrostatics. MOE uses a multi-grid algorithm to study and predict solvation effects without explicit treatment of water molecules.

iv. Conformational Analysis. The system can perform conformational analysis using Molecular Dynamics, Hybrid Monte Carlo, Stochastic or Systematic search methodologies.

v. Flexible Alignment of Small Molecules. The program uses an all-atom flexible alignment procedure to align or superimpose 3D structures.

vi. Diffraction Simulation. MOE can simulate X-Ray, Neutron or Electron diffraction experiments in either gas phase, amorphous liquid, powder and single crystal phases.

vii. Quantum Calculations. Ability to launch QM jobs such as MOPAC, GAMESS and Gaussian from MOE.

g. Methodology Development and Deployment: MOE's design allows the integration of other applications or the creation of new ones for Life Sciences.

i. Scientific Vector Language (SVL). SVL is a high-level scripting language to develop applications with MOE.

ii. Background Computing. MOE/batch can run batch or background calculations that do not require a graphical interface.

iii. Cluster Computing. MOE/smp allows the use of multiple computers to perform and carry out large-scale calculations.

iv. Computer Platforms. MOE can be used with Intel computers running Microsoft Windows or Linux as well as IBM eServer, Sun Microsystems, Hewlett-Packard, MOE Os X and Silicon Graphics computers running Unix.

IV. Review: MOE integrates under one platform tool sets for the study of macro-molecules and the design of promising inhibitors using combinatorial chemistry and receptor-ligand information with ADME and QSAR models. The MOE

system can operate under a wide range of computer platforms to minimize the IT barrier. The capability of running calculations in batch mode is a useful option to maximize the use of the system during non-peak hours (i.e., nights, weekends, etc.). Scalability is another feature of the system since calculations can be carried out using a computer farm. The system requires the user learn the SVL language to develop applications, something that medicinal and combinatorial chemists are not always receptive to do. However, the language is efficient and intuitive to learn and CCG provides customized training to commercial users.

Figure 2.36. CCG

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2.9 Cheminnovation Software

I. Cheminnovation Software, Inc;

II. Product Summaries: Cheminnovation Software, Inc provides software for chemistry graphics, molecular modeling, chemical nomenclature, and chemical and biological information management through the Internet. Products include:

a. CBIS (Chemical and Biological Informatics Systems) provides a suite of Web-based applications for managing chemical and biological materials and data throughout their lifespan. A full CBIS datasheet can be found at

b. ChemmInnovation's desktop products are integrated into the enterprise solution CBIS. View more information on CBIS

i. Chem 4-D Draws Chemical Structures Intelligently.

ii. Nomenclator Module assigns systematic names to structures according to IUPAC nomenclature rules.

iii. NameExpert Module understands IUPAC nomenclature rules. If one enters an IUPAC chemical name, it creates the corresponding structure.

iv. Chem4D DB Module manages databases of molecular structures, graphics and information associated with the data. It helps one to search and reuse graphics one has created.

v. Chemsite is a 3D molecular modeling program that allows one to model, animate, render and export 3D molecular graphics for visualization and publication. One can build all types of organic molecules, from small molecules, to proteins and DNAs.

III. Key capabilities and offerings: a. CBIS Modules i. CBIS Compounds

Manages corporate compounds and their properties. Provides registration procedures for checking duplicate structures and assigning unique Ids. Assigns IUPAC names. Tracks inventory and withdrawal requests. Prints barcode labels for vials or plates. Searching capabilities that support substructure matching or property filtering. Provides links to lab notebooks and assay database.

ii. CBIS Reactions

Manages reaction schemes and batches. Tracks reactants, products, conditions and reaction progress. Searches reactants and products' structures or properties. Provides links to lab notebooks, compound databases, and reagent inventory.

iii. CBIS Reagents

Manages reagent inventory. Tracks amounts and withdrawal history. Links to vender databases. Supports multi-level locations and stock room functionalities. Tracks safety information and provide reports for meeting regulations.

iv. CBIS Biomaterials

Manages databases of proteins, plasmids, phages, other biological materials and their data. Provides links to compounds and assay data. Tools for sequence analysis and searching.

v. CBIS Sequences

Collections of tools for DNA and Protein sequence analysis, searching and presentation. Supports restriction enzyme mappings, open reading frames, primer design, sequence alignment, property calculations.

vi. CBIS Bioassays

Manages results for bioassays. Response curve fitting and EC50/IC50 determination. Table pivoting for multiple compounds and targets. Provides links to compounds, notebooks.

vii. CBIS Bioassay-HTS

Tracks HTS plates and their data. Primary screen tools for identifying active compounds. Secondary screen tools for determining activities.

viii. CBIS Documents

Manages databases of various types of documents. Supports advanced searching for document contents and abstracts, key words. Automatically tracks document types.

ix. CBIS Reports

Manages project reports or monthly reports. Supports multiple attachments of all types of documents. Provides links to compounds, reactions, and assays. Searches structures, sequences, and properties amount all linked items.

x. CBIS Notebooks

Manages different formats of notebooks. Chem4D can be used to create pages of text, structures, and graphics. Pages are searchable and can be viewed via a browser. Copies of physical notebooks can be stored and viewed on-line.

xi. Chemistry 4-D Draw

Full-featured structure drawing and presentation program. Supports IUPAC nomenclature (names to structures, structures to names). Integrated with CBIS. Supports personal databases of structures, reactions, and graphics.

xii. Safety & Regulation

Maintains compounds and reagents' safety datasheet. Provides reports of safety data for meeting regulations.

xiii. Software, Hardware Requirements: Client: PC with Windows NT/2000/XP, Macintosh; Server Hardware: Pentium III or Higher, 256 MB Memory (RAM), 1 GB Disk Space; Server Software: Windows NT/2000/XP Databases: ORACLE, Microsoft SQL Server, Others via ODBC.

b. Desktop Products i. Chem 4-D Graph module that creates multi-line graphs of different styles. It supports non-linear and linear curve fitting, response curve fitting and data analysis. The program allows you to create high-quality structures simply by entering molecular names. It assigns systematic names to structures. It includes a full set of tools for drawing, text and structure editing, and labeling. Many features including over a dozen features related to the drawing program are described on the web.

ii. Chemsite is a 3D molecular modeling program that allows one to model, animate, render and export 3D molecular graphics for visualization and publication. One can build all types of organic molecules, from small molecules, to proteins and DNAs. Interactive 3D modeling and realtime animation lets you use molecular building blocks or atom-by-atom construction to visualize complex structures - whether protein, DNA, organic or inorganic - as fully-realized, space-filling entities. One can create and playback movies of molecular dynamics simulations. Analysis features include tools and techniques formerly found only on workstation-level modelers. Full support for stereochemistry, for instance, with dashes and wedges around chiral centers and auto-determination of R and S stereo centers is a part of the ChemSite package. Chemsite provides measurement tools ranging from inter-atomic distance to molecular weight and energy calculation.

1. Modeling Features Molecular models may be constructed in a variety of ways. A sketching tool is provided with automatic 2D to 3D conversion for easy building of inorganic and organic molecules. Organic molecules may be built from common organic functional groups and fragments. Peptides and proteins may be built with both D and L amino acids. Single and double stranded DNA/RNA polynu-cleotides may be constructed with ease.

2. Visualization Features Models may be viewed as stick figures, balls and sticks, CPK or with polymers as ribbons or extrusions. With stick figures, molecular models may be rotated in real time with the mouse. The program features ray tracing and texture mapping for the utmost in molecular graphics realism. Rendering styles may be mixed as desired. With high resolution displays, photo realistic display of molecular models are easily created. Images may be printed, saved as .BMP or TARGA files, or exported through the clipboard to word processors and desktop publishing programs. ChemSite brings state of the art workstation quality graphics capabilities to the pc.

3. Molecular Mechanics Features ChemSite performs energy minimization and molecular dynamics simulation. Available force fields include Amber, mm2 and the ChemSite's default cm+ force field for accurate calculations with almost any molecule. The program performs real time animation of energy minimization and molecular dynamics simulation with small to medium size molecules. With large molecules such as proteins, movies of molecular dynamics simulations may be recorded to disk and played back for real time animation.

4. Supported File Formats ChemSite reads and writes the following file formats:

(a) ChemSite library (.lib)

(c) Brookhaven Protein databank (.ent and.pdb)

(f) Connectivity table (.ct)

IV. Review: A remarkable range of drawing and visualization tools as alternatives or adjuncts to other drawing packages. IUPAC name-to-structure conversion tools automatically run on large sets of molecules and are available with other packages like ChemDraw and ISIS-DRAW. Logistics such as plate mapping and barcode printing are supported, as well as tools for molecular visualization and simulation. A wider exposure of these tools, as their intrinsic value may be greater than is currently widely known. More obvious integration with smi file formats and other widely used tools would be useful as well. Both product offerings and enterprise solutions are available from Cheminnovation software.

Figure 2.38. Chemlnnovation
Figure 2.S9. ChemInnovation

2.10 ChemNavigator

I. ChemNavigator

II. Product Summaries: ChemNavigator develops and markets scientific software and database technology. The products include 3DPL, CncTranslate, CncMCS,

CncDiverse, iResearch Library, On-line iResearch System, and Virtual Screening


III. Key capabilities and offerings:

a. 3-Dimensional Protein-Ligand Map (3DPL): This service offers a rapid approach for selecting a population of targeted small molecules from starting sets of millions that are likely to bind to a protein surface. 3DPL technology uses a 3D protein structure and large databases of small molecule structures to perform rapid, flexible virtual screening against all likely binding sites on the protein surface. 3DPL uses a patented combination of 3D searching and flexible protein-ligand docking techniques to analyze up to 15 structures per second on a single Windows workstation computer CPU.

b. CncTranslate: This is a chemoinformatics utility program to perform file conversion among many chemical structure file formats and to calculate properties on chemical structure databases, generate 3D coordinates and normalize structures. CncTranslate offers a full command line interface and may be used as a chemoinformatics utility program within other applications.

c. CncMCS: This is a maximum common substructure analysis program designed to rapidly identify the maximum common chemical substructure, or common core, contained within a series of chemical structures. The input is a file of chemical structures. The output of the program is a structure file containing the maximum chemical substructure contained within all input structures. The program has many parameters that enable the determination and output of multiple potential common substructures. CncMCS may be used in conjunction with the CncTranslate R-Groups option to determine R-Group variation around a core substructure within a series of related molecules. This is commonly applied in structure activity relationship (SAR) analysis.

d. CncDiverse: CncDiverse is a software tool for the selection of diverse chemical libraries from within a database of chemical structures. CncDiverse uses fragment based molecular fingerprints to make similarity comparisons between a single molecule and all others in a database. The program uses the Tamimoto Coefficient to compare fingerprints and calculate a similarity index. This index is used discriminate among molecules and select the most diverse (or not similar) set of molecules within the input database. This application is used to select diverse libraries from starting sets of 8+ million structures.

e. iResearch Library: The iResearch Library is ChemNavigator's up-to-date compilation of commercially accessible screening compounds, building blocks and fine chemicals from international chemistry suppliers. The database currently tracks over 22 million chemical samples. Database licenses include access to regular updates, sourcing information, and ChemNavigator's optional Chemistry Procurement Service. The database may be licensed on CD/DVD ROM or accessed through an on-line iResearch System subscription.

f. On-line iResearch System: The iResearch System provides access to ChemNavigator's iResearch Library of commercial screening compounds, building blocks, and fine chemicals. Using a single search, once can search all databases for structures of interest, and perform compound selection for specific projects and download result sets for off-line use. The iResearch System also provides detailed information on all chemical suppliers to order products.

g. Virtual Screening Services: ChemNavigator offers a comprehensive set of virtual screening services using proprietary in silico screening technology. Uisng 3DPL ChemNavigator can design a virtual screening program based upon either a 3D model of the target protein or a series of 3D protein targets.

IV. Review:

3DPL, part of ChemNavigator's drug discovery offering, has several advantages over current in silico technologies: 600-fold increase in speed of compound docking, entire protein is considered when searching for binding site, on-the-fly flexing of small molecules reduces chance of missing good candidates, and batch processing of large proteomics databases is routine. iResearch Library, part of the chemoinformatics offering, is based on over 23.3 million structures and associated data from 108 chemistry suppliers. Completion of their efforts to screen millions of drug-like compounds against thousands of public and proprietary 3-D protein targets will lead to a new lead discovery database that will provide a continual view of new, potential lead compounds.

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 03 03 03 03 CM 04 04 04 05 05 Figure 2.42. ChemNavigator

2.11 Chimera-Dock-Zinc from UCSF

I. Chimera and Dock; and the program DOCK (developed by the Kuntz group, UCSF) provides possible ligand-receptor binding orientations. provides a free database of commercially-available compounds for virtual screening. The Chimera extension ViewDock allows selecting promising compounds from DOCK calculations and viewing them at the binding site. Also see: UCSF Collaboratory environment:

II. Product Summary: UCSF Chimera is a 3-D molecular visualization program available free of charge for academic, government, non-profit, and personal use. For commercial use a license agreement must be obtained. The program can interact with the output of other computational programs and can be customized using Python. Similar terms are available for Dock. ZINC contains over 3.3 million compounds in ready-to-dock, 3D formats.

III. Key Capabilities (for Chimera, see website for latest on Dock and Zinc)

a. Molecular Graphics:

i. Real-time molecular rendering (i.e., wire, stick, ball-and-stick, CPK, ribbons, and molecular surfaces).

ii. Provides an interface for model translation, scaling, and rotation, and includes a Side View viewing tool to adjust clipping planes and scaling.

iii. Capabilites include interactive color editing including transparency.

iv. Ability to save high-resolution images with high quality for presentations and publications.

v. Stereo viewing (side-by-side and time-sequential).

b. Chemical knowledge:

i. Determination of atom types including non-standard residues.

ii. Adds hydrogen atoms.

iii. High-quality hydrogen bond identification.

iv. Selection of atoms/bonds by element, atom type, functional group, and amino acid residue.

v. Interactive bond rotation, distance and angle measurements.

c. Sequence Viewer: The Multalign Viewer extension displays multiple sequence alignments, calculates and shows a consensus sequence and conservation histogram, and allows regions to be defined and colored.

d. Volume data: Volume Viewer shows 3D electron and light microscope data, x-ray density maps, electrostatic potential and other volumetric data. Isosurfaces, meshes and transparent solid display styles are provided and thresholds can be changed interactively.

e. Molecular Dynamics: Chimera can display molecular dynamics trajectories from several programs (e.g., AMBER, CHARMM, GROMOS, PDB formats). All analysis and display capabilities are available with trajectories.

f. Screening Drug Candidates: The program DOCK (developed by the Kuntz group, UCSF) provides possible ligand-receptor binding orientations. The Chimera extension ViewDock allows selecting promising compounds from DOCK calculations and viewing them at the binding site.

g. Collaboratory: The Collaboratory is an extension to Chimera that allows researchers share molecular modeling session over a standard network connection. Users have equal control over the molecular structures and all modifications done in a session are instantly seen by all users.

h. Programmability / Extensibility: Chimera is largely implemented in Python with certain components coded in C++ . All of Chimera's functionality is accessible through Python and users can implement their own algorithms and extensions without any Chimera code changes allowing their extensions to work across Chimera releases.

IV Review: UCSF Chimera is an interactive molecular graphics program available for many operating systems (e.g., Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix). Chimera is primarily a molecular visualization tool for small molecules and biological macromolecules. Tutorials and help sheets are both available to assist new users, which is important because the program has many capabilities, and first-time users may not know where to begin; frametut.html. Chimera's menu-based interface is useful for new and more casual users, while the command-based interface allows experienced users to perform complex tasks quickly. Files of Chimera commands can also be created for later input to the program.

Figure 2.45. Chimera-Dock-Zinc from UCSF
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