Phase 2 of the Project

As of 1 July 2002 we have moved into Phase 2 of the Screensaver Project. In Phase 1, using the THINK software, some 3.5 billion drug-like molecules, mostly as yet unsynthesised, have been tested against 12 proteins which are known as suitable targets for anti-cancer drugs. Each single molecule has been tested a multiple of times to ensure a complete coverage and to give some quality reassurance. Those molecules predicted to bind better than a somewhat arbitrary threshold have been termed 'hits', with the most promising having negative binding energies on our scale.

A major goal of Phase 2 using the LigandFit software is to refine these data to produce a more manageable list of promising candidates for synthesis and testing which will of course be costly and require experimental collaborators including some from industry.

More Information about the Accelrys LigandFit software

The automatic docking of a flexible ligand into a protein active site is a critical step in the process of structure-based design.

LigandFit provides structure-based design capabilities including, active site finding, flexible docking and scoring capabilities, allowing evaluation of compounds against a receptor site. Scores from LigandFit provide direct insight into the complementary features of ligands and their potential as lead candidates.

LigandFit provides a cavity search algorithm for finding binding sites. Possible sites are proposed to the user who can choose location of a binding site, or to use a binding site already defined by a ligand. In both cases, the site model can be edited to suit the user's requirements. This is especially useful when a model or experimental structure of the protein has been obtained but the binding site has not been identified.

LigandFit uses the energy of the ligand-receptor complex to automatically find the best binding modes of the ligand to the receptor.

LigandFit uses a stochastic conformational search technique and retains the best results from the conformational sampling. A grid method is used for the evaluation of non bonded interactions between the rigid protein and the movable atoms from the flexible ligand. Grid methods have proven to be very effective for fast and accurate approximations of protein-ligand interactions compared to full force field representations (1-3).

1. B.A. Luty, Z.R. Wasserman, P.F.W. Stouten, C.N. Hodge, M. Zacharias and J.A. McCammon, "Molecular Mechanics/Grid Method for the Evaluation of Ligand-Receptor Interactions", J. Comp. Chem. 16, 454-464, 1995.
2. N. Pattabiraman, M. Levitt, T.E. Ferrin, and R. Langridge, "Computer Graphics in Real-time Docking with Energy Calculation and Minimization", J. Comp. Chem. 6, 432-436, 1985.
3. E.C. Meng, B.K. Shoichet, I.D. Kuntz, "Automated Docking with Grid-Based Energy Evaluation", J. Comp. Chem. 13, 505-524, 1992.
4. C.M. Venkatachalam, X. Jiang, T. Oldfield, and M. Waldman, "LigandFit: A Novel method for the Shape-Directed Rapid Docking of Ligands to Protein Active Sites", J. Mol. Graphics Modeling, 2002.
   
   

The new Ligand Fit software running in the UD.com agent.

Find out more about the LigandFit software running on your machine at the Ud.com web site.

http://www.grid.org/projects/cancer/ligandfit.htm