ChemNavigator® 3DPL™(3-Dimensional Protein-Ligand Search)

By: Mike Willis, Chemfiles Volume 7 Article 4

Mike Willis
Market Segment Manager
Mike Willis@sial.com

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3DPL Provides fast identification of targeted molecules

3DPL offers a rapid approach for selecting a population of targeted molecules from starting sets of millions of small molecule structures. 3DPL technology uses a protein structure and large databases of small molecule structures to perform rapid, fl exible virtual screening against all likely binding sites on the protein surface. 3DPL is used to identify highly targeted sets of small molecule structures likely to bind the protein surface. Discovery companies can assay sets of hundreds to low thousands of high value structures and avoid screening larger sets of tens of thousands of diverse compounds.

3DPL is designed to allow drug discovery companies to identify a target-focused set of chemistry and move to bioassay and lead identifi cation as quickly and effi ciently as possible. 3DPL has several major advantages that allow for rapid identifi cation of potential active molecules:

Advantages of 3DPL Searching

  • Knowledge of active site not required: 3DPL includes technology for automated identifi cation of all sites on the protein surface of appropriate size for binding with a therapeutic molecule. This Convex Hull technology identifi es all potential binding sites that can be used in fl exible screening, and it eliminates the need for an identifi ed binding site as input for the screening experiment.
  • Entire protein surface may be considered: Each small molecule is compared against all potential binding sites on the 3D protein surface to look for potential binding interactions. This approach off ers the opportunity to identify ligands that would have been overlooked by virtual screening technologies that focus on only one or more pre-defi ned active sites on the protein surface.
  • Automatic conformational analysis: Each small molecule ligand is fl exed, in an energetically directed approach, and re-oriented thousands of times in the search for potential matches between the ligand and the protein surface.
  • Speed enables in silico screening of millions of small molecules: 3DPL employs a unique and patented derivative fi eld grid to direct small molecules to favorable binding conformations. The use of these grids signifi cantly reduces computational time. Running on a single 1.4 GHz server, 3DPL is able to evaluate over 8 million chemical structures for binding across the entire protein surface in less than 4 days—a 600-fold increase over the fastest technology available today. Much larger structure sets can be run, which eliminates the need to fi lter out large numbers of potentially valuable samples before the virtual screening experiment.
  • 3D Version of on-line iResearch™ Library included: iResearch Subscribers may now access a special on-line version of the iResearch Library that is confi gured to use with 3DPL. This provides access to over 20 million 3D ligands for use in virtual screening.

Input to the system is a 3D protein model and a set of 3D small molecule structures; output is a selection of scored small molecule structures that have been calculated to show binding affi nity for the protein surface. 3DPL can be used with ChemNavigator's iResearch Library of over million unique structures to provide access to the greatest diversity of commercially available small molecule compounds.

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