Practical Aspects of the SAMPL Challenge: Providing an Extensive Experimental Data Set for the Modeling Community

To provide an experimental basis for a comprehensive molecular modeling evaluation study, 500 fragments from the Maybridge fragment library were soaked into crystals of bovine pancreatic trypsin and the structures determined by X-ray crystallography. The soaking experiments were performed in both single and pooled aliquots to determine if combination of fragments is an appropriate strategy. A further set of data was obtained from co-crystallizing the pooled fragments with the protein. X-ray diffraction data were collected on approximately 1000 crystals at the Australian Synchrotron, and these data were subsequently processed, and the preliminary analysis was performed with a custom software application (Jigsaw), which combines available software packages for structure solution and analysis.

[1]  M. Congreve,et al.  A 'rule of three' for fragment-based lead discovery? , 2003, Drug discovery today.

[2]  Wolfgang Kabsch,et al.  Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants , 1993 .

[3]  Jan Schultz,et al.  Integration of fragment screening and library design. , 2007, Drug discovery today.

[4]  Kevin Cowtan,et al.  research papers Acta Crystallographica Section D Biological , 2005 .

[5]  Fred L. Drake,et al.  The Python Language Reference Manual , 1999 .

[6]  B. Shoichet,et al.  Molecular docking and ligand specificity in fragment-based inhibitor discovery. , 2009, Nature chemical biology.

[7]  D. Rauh,et al.  Trypsin Mutants for Structure-Based Drug Design: Expression, Refolding and Crystallisation , 2002, Biological chemistry.

[8]  Anthony Nicholls,et al.  What do we know and when do we know it? , 2008, J. Comput. Aided Mol. Des..

[9]  L. Lally.  The CCP 4 Suite — Computer programs for protein crystallography , 1998 .

[10]  R. Huber,et al.  Crystal structures of factor Xa specific inhibitors in complex with trypsin: structural grounds for inhibition of factor Xa and selectivity against thrombin , 1995, FEBS letters.

[11]  J. Northrop,et al.  ISOLATION OF PROTEIN CRYSTALS POSSESSING TRYPTIC ACTIVITY. , 1931, Science.

[12]  A. Nicholls,et al.  Automated ligand placement and refinement with a combined force field and shape potential. , 2006, Acta crystallographica. Section D, Biological crystallography.

[13]  M. Kunitz,et al.  THE EFFECT OF CALCIUM AND OTHER IONS ON THE AUTOCATALYTIC FORMATION OF TRYPSIN FROM TRYPSINOGEN , 1941, The Journal of general physiology.

[14]  A. Hopkins,et al.  The druggable genome , 2002, Nature Reviews Drug Discovery.

[15]  Janet Newman,et al.  Phoenito experiments: combining the strengths of commercial crystallization automation. , 2008, Acta crystallographica. Section F, Structural biology and crystallization communications.

[16]  F. Markwardt,et al.  Comparative studies on the inhibition of trypsin, plasmin, and thrombin by derivatives of benzylamine and benzamidine. , 1968, European journal of biochemistry.

[17]  J. Luft,et al.  A method to produce microseed stock for use in the crystallization of biological macromolecules. , 1999, Acta crystallographica. Section D, Biological crystallography.

[18]  David Weininger,et al.  SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules , 1988, J. Chem. Inf. Comput. Sci..