THE KNOWITALL INFORMATICS SYSTEM
Gregory M. Banik, Karl Nedwed, Ty Abshear; Bio-Rad Laboratories, Informatics Division, Philadelphia, PA 19104, USA
Bio-Rad Laboratories' Informatics Division, the world leader inspectral databases, offers the leading source of data that can be used as a reference in the KnowItAll Informatics System, Analytical Edition-the first, fully integrated environment for analytical techniques such as IR, NMR, MS, UV/Vis, GC, Raman, and Near IR. Now users can have it all and know it all in one place-search, access reference spectra, build databases with spectra and property information, perform functional group analysis, and generate high-quality reports to share all users know with their colleagues.
The KnowItAll Informatics System is modular and customizable so users can easily transfer information from plug-in to plug-in without having to leave the main interface and without having to open another program. Because of the unique design of the KnowItAll Informatics System, third-party software functionality can quickly and easily be plugged into the powerful KnowItAll architecture. The resulting recent enhancements to the KnowItAll product line will be discussed.
QUASI2 - A NEW TOOL FOR LIGAND-BASED AND LIGAND-FOCUSSED DESIGN
Nicholas C. Perry, Nikolay P. Todorov, Paulette A. Greenidge, David G. Lloyd, Philip M. Dean; De Novo Pharmaceuticals, Cambridge CB4 9ZR, UK
We have developed a new program, Quasi2, for the rapid creation of active site models through the global superposition of multiple flexible ligands. Quasi2 uses a simulated annealing process to optimise the superposition of structures as a function of multiple variables, including conformation, protonation state, tautomeric state and choice of mapping of structural features. A particular feature of the program is its ability to fit molecules showing only partial similarity, thus mimicking the situation in which different ligands bind to the same target site but utilize different binding interactions. Quasi2 has been validated by application to a diverse set of biomolecular targets including GPCRs and proteases.
Previously we have illustrated the success of the program SLATE in the ligand-based design and subsequent synthesis of novel modulators of the histamine H3 receptor (De Esch et al, J Med Chem 2001 44, 1666-1674). Quasi2 is able to reproduce the SLATE active site model for antagonism at the human H3 receptor in a fully automated manner and in a fraction of the time required for the SLATE procedure. We have been able to show that qualitatively similar models can be generated independently of the division of the data into training and test sets. Active site models generated through Quasi2 are compatible with De Novo's core design technology Skelgen for the ab initio design of novel therapeutic agents.
The capacity of Quasi2 to handle highly flexible molecules is demonstrated by its ability to superimpose a series of protease inhibitors (15-23 rotatable bonds) in a manner consistent with the crystallographically observed conformations. When one or more crystal structures are available for a given target, a study of the interactions utilised by co-crystallised ligands is often used to identify key site points to be used in novel design strategies. If additional ligands are known, these may be used in addition to the co-crystallised ligands to generate a Quasi2 active site model. The orientation of the additional ligands in this model corresponds to a validated docked conformation and can identify additional site features for use in structure-based design.
Thus Quasi2 has proved useful in the field of ligand-based design (in the absence of a target structure) and in ligand-focussed design (where a structure is available but further information can be provided by the consideration of additional ligands).