A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction.

In this paper, we describe the first prospective application of the shape-comparison program ROCS (Rapid Overlay of Chemical Structures) to find new scaffolds for small molecule inhibitors of the ZipA-FtsZ protein-protein interaction, a proposed antibacterial target. The shape comparisons are made relative to the crystallographically determined, bioactive conformation of a high-throughput screening (HTS) hit. The use of ROCS led to the identification of a set of novel, weakly binding inhibitors with scaffolds presenting synthetic opportunities to further optimize biological affinity and lacking development issues associated with the HTS lead. These ROCS-identified scaffolds would have been missed using other structural similarity approaches such as ISIS 2D fingerprints. X-ray crystallographic analysis of one of the new inhibitors bound to ZipA reveals that the shape comparison approach very accurately predicted the binding mode. These experimental results validate this use of ROCS for chemotype switching or "lead hopping" and suggest that it is of general interest for lead identification in drug discovery endeavors.

[1]  B. Masek,et al.  Molecular shape comparison of angiotensin II receptor antagonists. , 1993, Journal of medicinal chemistry.

[2]  J. Navaza,et al.  AMoRe: an automated package for molecular replacement , 1994 .

[3]  J. A. Grant,et al.  A Gaussian Description of Molecular Shape , 1995 .

[4]  J. Lutkenhaus,et al.  Bacterial cell division and the Z ring. , 1997, Annual review of biochemistry.

[5]  C. Hale,et al.  Direct Binding of FtsZ to ZipA, an Essential Component of the Septal Ring Structure That Mediates Cell Division in E. coli , 1997, Cell.

[6]  Thomas Meyer,et al.  Structure-based design of potent CDK1 inhibitors derived from olomoucine , 2000, J. Comput. Aided Mol. Des..

[7]  A G Cochran,et al.  Antagonists of protein-protein interactions. , 2000, Chemistry & biology.

[8]  Yan Zhang,et al.  The bacterial cell‐division protein ZipA and its interaction with an FtsZ fragment revealed by X‐ray crystallography , 2001, The EMBO journal.

[9]  P. Kollman,et al.  Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA. , 2001, Journal of the American Chemical Society.

[10]  James G. Nourse,et al.  Reoptimization of MDL Keys for Use in Drug Discovery , 2002, J. Chem. Inf. Comput. Sci..

[11]  P. Toogood.  Inhibition of protein-protein association by small molecules: approaches and progress. , 2002, Journal of medicinal chemistry.

[12]  L. Mosyak,et al.  Development of a fluorescence polarization assay to screen for inhibitors of the FtsZ/ZipA interaction. , 2003, Analytical biochemistry.

[13]  J. Alvarez,et al.  Structure-based design of carboxybiphenylindole inhibitors of the ZipA-FtsZ interaction. , 2003, Organic & biomolecular chemistry.

[14]  A. Hopkins,et al.  Ligand efficiency: a useful metric for lead selection. , 2004, Drug discovery today.

[15]  T. Rush,et al.  Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA-FtsZ interaction. , 2004, Bioorganic & medicinal chemistry letters.

[16]  Gregory Tawa,et al.  Solvation-Based Scoring for High Throughput Docking , 2005 .