Coupling structure-based design with combinatorial chemistry: application of active site derived pharmacophores with informative library design.

Protein structural information is combined with combinatorial library design in the following protocol. Active site maps are generated from protein structures. All possible 2-, 3- and 4-point pharmacophores are enumerated from the active site map and encoded as bit strings. The pharmacophores define a design space that can be used to select compounds using an informative library design tool. The method was evaluated against a collection of compounds assayed previously against a cyclin-dependent kinase target, CDK-2, starting with 23 X-ray co-crystal structures. Performance was assessed based on the number of active scaffolds selected after four rounds of iterative informative library design. The method selects compounds from 12 out of the 15 active scaffolds from the CDK-2 library and outperforms a two-dimensional similarity search and docking calculations.

[1]  S. Kim,et al.  High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design. , 1996, Journal of medicinal chemistry.

[2]  Philip D. Jeffrey,et al.  Crystal structure of the p27Kip1 cyclin-dependent-kinase inibitor bound to the cyclin A–Cdk2 complex , 1996, Nature.

[3]  J. Mason,et al.  New 4-point pharmacophore method for molecular similarity and diversity applications: overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures. , 1999, Journal of medicinal chemistry.

[4]  M. Karplus,et al.  Functionality maps of binding sites: A multiple copy simultaneous search method , 1991, Proteins.

[5]  J S Mason,et al.  Library design and virtual screening using multiple 4-point pharmacophore fingerprints. , 1999, Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing.

[6]  D. Osguthorpe,et al.  Structure and energetics of ligand binding to proteins: Escherichia coli dihydrofolate reductase‐trimethoprim, a drug‐receptor system , 1988, Proteins.

[7]  Steven L. Teig.  Informative Libraries are More Useful than Diverse Ones , 1998 .

[8]  Gennady M Verkhivker,et al.  Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. , 1995, Chemistry & biology.

[9]  Robert Stanton,et al.  Conformational analysis by intersection: CONAN , 2003, J. Comput. Chem..

[10]  Philip M. Dean,et al.  Three-dimensional hydrogen-bond geometry and probability information from a crystal survey , 1996, J. Comput. Aided Mol. Des..

[11]  L Meijer,et al.  Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. , 2000, Chemistry & biology.

[12]  T. Kennedy.  Managing the drug discovery/development interface , 1997 .

[13]  S H Kim,et al.  Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. , 1998, Science.

[14]  S. Elledge,et al.  Inhibition of cyclin-dependent kinases by p21. , 1995, Molecular biology of the cell.

[16]  F. Bushman,et al.  Developing a dynamic pharmacophore model for HIV-1 integrase. , 2000, Journal of medicinal chemistry.

[17]  D. Kostrewa,et al.  Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. , 2000, Journal of medicinal chemistry.

[18]  Arup K. Ghose,et al.  Adapting Structure-Based Drug Design in the Paradigm of Combinatorial Chemistry and High-Throughput Screening: An Overview and New Examples with Important Caveats for Newcomers to Combinatorial Library Design Using Pharmacophore Models or Multiple Copy Simultaneous Search Fragments , 1999 .

[19]  J. Ippolito,et al.  Hydrogen bond stereochemistry in protein structure and function. , 1990, Journal of molecular biology.

[20]  Malcolm J. McGregor,et al.  Pharmacophore Fingerprinting. 1. Application to QSAR and Focused Library Design , 1999, J. Chem. Inf. Comput. Sci..

[21]  Jonathan S. Mason,et al.  Ligand-Receptor 3-D Similarity Studies Using Multiple 4-Point Pharmacophores , 1999, Pacific Symposium on Biocomputing.

[22]  J. H. Van Drie,et al.  Addressing the Challenges Posed by Combinatorial Chemistry: 3D Databases, Pharmacophore Recognition and Beyond , 1998 .

[23]  Pieter F. W. Stouten,et al.  Fast prediction and visualization of protein binding pockets with PASS , 2000, J. Comput. Aided Mol. Des..