Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase.

Herein, we describe a combi-nation of fragment-growing and fragment-linking approachesthat led to the discovery of a new series of inhibitors ofM. tuberculosis PS for the further validation of PS as apotential drug target for TB.We devised a systematic strategy for fragment screening,validation, and characterization

[1]  David Eisenberg,et al.  A Novel Inhibitor of Mycobacterium tuberculosis Pantothenate Synthetase , 2007, Journal of biomolecular screening.

[2]  G. Fogliatto,et al.  WaterLOGSY as a method for primary NMR screening: Practical aspects and range of applicability , 2001, Journal of biomolecular NMR.

[3]  W. Denny,et al.  A roadmap for drug discovery and its translation to small molecule agents in clinical development for tuberculosis treatment. , 2008, Tuberculosis.

[4]  R. Glen,et al.  Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. , 1995, Journal of molecular biology.

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

[6]  Chris Abell,et al.  Inhibition of Mycobacterium tuberculosis Pantothenate Synthetase by Analogues of the Reaction Intermediate , 2008, Chembiochem : a European journal of chemical biology.

[7]  Jonathan Bard,et al.  Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. , 2004, Analytical biochemistry.

[8]  L. Mario Amzel,et al.  Impact of linker strain and flexibility in the design of a fragment-based inhibitor , 2009, Nature chemical biology.

[9]  Christopher Dye,et al.  The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. , 2003, Archives of internal medicine.

[10]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[11]  Positional isotope exchange analysis of the pantothenate synthetase reaction. , 2003, Biochemistry.

[12]  Glyn Williams,et al.  Fragment-based screening using X-ray crystallography and NMR spectroscopy. , 2007, Current opinion in chemical biology.

[13]  C. Abell,et al.  The design and synthesis of inhibitors of pantothenate synthetase. , 2006, Organic & biomolecular chemistry.

[14]  P. Hajduk,et al.  A decade of fragment-based drug design: strategic advances and lessons learned , 2007, Nature Reviews Drug Discovery.

[15]  Solomon Nwaka,et al.  Innovative lead discovery strategies for tropical diseases , 2006, Nature Reviews Drug Discovery.

[16]  Harren Jhoti,et al.  High-throughput crystallography for lead discovery in drug design , 2002, Nature Reviews Drug Discovery.

[17]  Steady-state and pre-steady-state kinetic analysis of Mycobacterium tuberculosis pantothenate synthetase. , 2001 .

[18]  Chris Abell,et al.  Fragment-based approaches to enzyme inhibition. , 2007, Current opinion in biotechnology.

[19]  S. Franzblau,et al.  5-tert-butyl-N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxamide derivatives as novel potent inhibitors of Mycobacterium tuberculosis pantothenate synthetase: initiating a quest for new antitubercular drugs. , 2008, Journal of medicinal chemistry.

[20]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .