Fragment-Based Cocktail Crystallography by the Medical Structural Genomics of Pathogenic Protozoa Consortium

Christophe L.M.J. Verlinde; Erkang Fan; Sayaka Shibata; Zhongsheng Zhang; Zhihua Sun; Wei Deng; Jennifer Ross; Jessica Kim; Liren Xiao; Tracy L. Arakaki; Jurgen Bosch; Jonathan M. Caruthers; Eric T. Larson; Isolde LeTrong; Alberto Napuli; Angela Kelley; Natasha Mueller; Frank Zucker; Wesley C. Van Voorhis; Frederick S. Buckner; Ethan A. Merritt; Wim G.J. Hol

doi:10.2174/156802609790102383

ISSN: 1568-0266
E-ISSN: 1873-4294

Fragment-Based Cocktail Crystallography by the Medical Structural Genomics of Pathogenic Protozoa Consortium
Authors: Christophe L.M.J. Verlinde¹, Erkang Fan², Sayaka Shibata³, Zhongsheng Zhang⁴, Zhihua Sun⁵, Wei Deng⁶, Jennifer Ross⁷, Jessica Kim⁸, Liren Xiao⁹, Tracy L. Arakaki¹⁰, Jurgen Bosch¹¹, Jonathan M. Caruthers¹², Eric T. Larson¹³, Isolde LeTrong¹⁴, Alberto Napuli¹⁵, Angela Kelley¹⁶, Natasha Mueller¹⁷, Frank Zucker¹⁸, Wesley C. Van Voorhis¹⁹, Frederick S. Buckner²⁰, Ethan A. Merritt²¹ and Wim G.J. Hol²²
View Affiliations Hide Affiliations

¹ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ² Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ³ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ⁴ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ⁵ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ⁶ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ⁷ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ⁸ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ⁹ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹⁰ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹¹ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹² Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹³ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹⁴ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹⁵ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹⁶ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹⁷ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹⁸ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ¹⁹ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ²⁰ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ²¹ Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. ²² Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Source: Current Topics in Medicinal Chemistry, Volume 9, Issue 18, Dec 2009, p. 1678 - 1687
DOI: https://doi.org/10.2174/156802609790102383
- Available online: 01 Dec 2009

Abstract

The history of fragment-based drug discovery, with an emphasis on crystallographic methods, is sketched, illuminating various contributions, including our own, which preceded the industrial development of the method. Subsequently, the creation of the BMSC fragment cocktails library is described. The BMSC collection currently comprises 68 cocktails of 10 compounds that are shape-wise diverse. The utility of these cocktails for initiating lead discovery in structure-based drug design has been explored by soaking numerous protein crystals obtained by our MSGPP (Medical Structural Genomics of Pathogenic Protozoa) consortium. Details of the fragment selection and cocktail design procedures, as well as examples of the successes obtained are given. The BMSC Fragment Cocktail recipes are available free of charge and are in use in over 20 academic labs.

Article metrics loading...

/content/journals/ctmc/10.2174/156802609790102383

2009-12-01

2025-09-27

From This Site

/content/journals/ctmc/10.2174/156802609790102383

dcterms_title,dcterms_subject,pub_keyword

-contentType:Contributor -contentType:Concept -contentType:Institution

10

5

Full text loading...

/content/journals/ctmc/10.2174/156802609790102383

Article Type: Research Article

Keyword(s): drug design; history; leishmaniasis; malaria; Structural genomics; trypanosomiasis

Fragment-Based Cocktail Crystallography by the Medical Structural Genomics of Pathogenic Protozoa Consortium

Abstract

From This Site

Most Read This Month

Most Cited Most Cited RSS feed

Subunit Composition, Distribution and Function of GABA-A Receptor Subtypes

Structure and Function of HIV-1 Integrase

Mapping of the Benzodiazepine Recognition Site on GABA-A Receptors

Iminosugars and Relatives as Antiviral and Potential Anti-infective Agents

LncRNA as a Therapeutic Target for Angiogenesis

Design, Synthesis and Biological Evaluation of Iminosugar-Based Glycosyltransferase Inhibitors

Naturally Occurring Iminosugars and Related Compounds: Structure, Distribution, and Biological Activity

Macrolide Antibiotics: Binding Site, Mechanism of Action, Resistance

Therapeutic Applications of Imino Sugars in Lysosomal Storage Disorders

Photoaffinity Labeling in Drug Discovery and Developments: Chemical Gateway for Entering Proteomic Frontier